This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ClinVar Genomic variation as it relates to human health
NM_000791.4(DHFR):c.-416C>G
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(12)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Benign/Likely benign
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000791.4(DHFR):c.-416C>G
Variation ID: 635180 Accession: VCV000635180.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q14.1 5: 80654905 (GRCh38) [ NCBI UCSC ] 5: 79950724 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 29, 2019 Sep 29, 2024 Oct 14, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000791.4:c.-416C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
5 prime UTR NM_002439.5:c.178G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002430.3:p.Ala60Pro missense NM_001290354.2:c.-522C>G 5 prime UTR NM_001290357.2:c.-416C>G 5 prime UTR NM_002439.4:c.178G>C NR_110936.2:n.79C>G non-coding transcript variant NC_000005.10:g.80654905G>C NC_000005.9:g.79950724G>C NG_016607.2:g.5431G>C NG_023304.1:g.5077C>G NG_105205.1:g.501G>C NG_105205.2:g.528G>C - Protein change
- A60P
- Other names
- -
- Canonical SPDI
- NC_000005.10:80654904:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.02077 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00949
Exome Aggregation Consortium (ExAC) 0.01232
The Genome Aggregation Database (gnomAD), exomes 0.01259
1000 Genomes Project 0.02077
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| DHFR | - | - |
GRCh38 GRCh37 |
111 | 660 | |
| MSH3 | - | - |
GRCh38 GRCh37 |
4010 | 4695 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
May 21, 2019 | RCV000786036.2 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 27, 2021 | RCV001013164.5 | |
| Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 11, 2023 | RCV001357722.9 | |
| Benign (1) |
criteria provided, single submitter
|
Oct 14, 2023 | RCV001803978.11 | |
| Likely benign (2) |
criteria provided, single submitter
|
Aug 15, 2023 | RCV001796212.6 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Benign
(Apr 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046955.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Benign
(Feb 27, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002535987.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Likely benign
(Mar 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002006233.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
|
|
|
Likely benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002570197.4
First in ClinVar: Sep 17, 2022 Last updated: Aug 18, 2023 |
|
|
|
Benign
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Constitutional megaloblastic anemia with severe neurologic disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048756.4
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Sep 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001173712.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Benign
(Jul 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004459332.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005227190.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
|
Uncertain significance
(May 21, 2019)
|
no assertion criteria provided
Method: research
|
Cavernous Sinus Meningioma
Affected status: yes
Allele origin:
somatic
|
Genome Sciences Centre, British Columbia Cancer Agency
Accession: SCV000924577.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553275.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH3 p.Ala60Pro variant was identified in 1 of 126 proband chromosomes (frequency: 0.0079) from CRC specimens collected from Iranian, Shirazi (Iranian Caucasians) (Ashktorab_2017_28002797). The … (more)
The MSH3 p.Ala60Pro variant was identified in 1 of 126 proband chromosomes (frequency: 0.0079) from CRC specimens collected from Iranian, Shirazi (Iranian Caucasians) (Ashktorab_2017_28002797). The variant was also identified in dbSNP (ID: rs2001675) and MutDB. The variant was not identified in ClinVar, Clinvitae, COGR, Cosmic, LOVD 3.0, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, ADPKD Mutation Database, PKD1-LOVD, RWTH AAachen University ARPKD database, IARC TP53 Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 1612 of 135934 chromosomes (27 homozygous) at a frequency of 0.01186 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 122 of 5708 chromosomes (freq: 0.02137), European (non-Finnish) in 1022 of 61450 chromosomes (freq: 0.01663), Other in 46 of 3482 chromosomes (freq: 0.01321), South Asian in 178 of 16450 chromosomes (freq: 0.01082), Latino in 102 of 16548 chromosomes (freq: 0.006164), African in 42 of 8462 chromosomes (freq: 0.004963), European (Finnish) in 73 of 14892 chromosomes (freq: 0.004902) and East Asian in 27 of 8942 chromosomes (freq: 0.003019). Ashktorab et al. identified a variant at loci 79950724 with a G to C change in the MutS_I domain with a frequency of 0.02 (1/63, heterozygous) (Ashktorab_2017_28002797). This variant in MSH3 is predicted by in silico functional analysis to disrupt the MSH2-MSH3 association to form the MutSβ complex which would result in a defective DNA mismatch repair. It appears to suggest altered static interactions within the MSH2-MSH3 heterodimers. The variant occurs at the site of MSH2 binding, and is likely to disturb the complex formed by MSH3 with MSH2. The p.Ala60 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Ashktorab, Hassan, et al. "Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer." Oncotarget 8.5 (2017): 7852. (less)
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034625.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035446.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
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Comment:
Comment:
The MSH3 p.Ala60Pro variant was identified in 1 of 126 proband chromosomes (frequency: 0.0079) from CRC specimens collected from Iranian, Shirazi (Iranian Caucasians) (Ashktorab_2017_28002797). The variant was also identified in dbSNP (ID: rs2001675) and MutDB. The variant was not identified in ClinVar, Clinvitae, COGR, Cosmic, LOVD 3.0, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, ADPKD Mutation Database, PKD1-LOVD, RWTH AAachen University ARPKD database, IARC TP53 Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 1612 of 135934 chromosomes (27 homozygous) at a frequency of 0.01186 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 122 of 5708 chromosomes (freq: 0.02137), European (non-Finnish) in 1022 of 61450 chromosomes (freq: 0.01663), Other in 46 of 3482 chromosomes (freq: 0.01321), South Asian in 178 of 16450 chromosomes (freq: 0.01082), Latino in 102 of 16548 chromosomes (freq: 0.006164), African in 42 of 8462 chromosomes (freq: 0.004963), European (Finnish) in 73 of 14892 chromosomes (freq: 0.004902) and East Asian in 27 of 8942 chromosomes (freq: 0.003019). Ashktorab et al. identified a variant at loci 79950724 with a G to C change in the MutS_I domain with a frequency of 0.02 (1/63, heterozygous) (Ashktorab_2017_28002797). This variant in MSH3 is predicted by in silico functional analysis to disrupt the MSH2-MSH3 association to form the MutSβ complex which would result in a defective DNA mismatch repair. It appears to suggest altered static interactions within the MSH2-MSH3 heterodimers. The variant occurs at the site of MSH2 binding, and is likely to disturb the complex formed by MSH3 with MSH2. The p.Ala60 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Ashktorab, Hassan, et al. "Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer." Oncotarget 8.5 (2017): 7852.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
The MSH3 p.Ala60Pro variant was identified in 1 of 126 proband chromosomes (frequency: 0.0079) from CRC specimens collected from Iranian, Shirazi (Iranian Caucasians) (Ashktorab_2017_28002797). The variant was also identified in dbSNP (ID: rs2001675) and MutDB. The variant was not identified in ClinVar, Clinvitae, COGR, Cosmic, LOVD 3.0, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, ADPKD Mutation Database, PKD1-LOVD, RWTH AAachen University ARPKD database, IARC TP53 Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 1612 of 135934 chromosomes (27 homozygous) at a frequency of 0.01186 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 122 of 5708 chromosomes (freq: 0.02137), European (non-Finnish) in 1022 of 61450 chromosomes (freq: 0.01663), Other in 46 of 3482 chromosomes (freq: 0.01321), South Asian in 178 of 16450 chromosomes (freq: 0.01082), Latino in 102 of 16548 chromosomes (freq: 0.006164), African in 42 of 8462 chromosomes (freq: 0.004963), European (Finnish) in 73 of 14892 chromosomes (freq: 0.004902) and East Asian in 27 of 8942 chromosomes (freq: 0.003019). Ashktorab et al. identified a variant at loci 79950724 with a G to C change in the MutS_I domain with a frequency of 0.02 (1/63, heterozygous) (Ashktorab_2017_28002797). This variant in MSH3 is predicted by in silico functional analysis to disrupt the MSH2-MSH3 association to form the MutSβ complex which would result in a defective DNA mismatch repair. It appears to suggest altered static interactions within the MSH2-MSH3 heterodimers. The variant occurs at the site of MSH2 binding, and is likely to disturb the complex formed by MSH3 with MSH2. The p.Ala60 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Ashktorab, Hassan, et al. "Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer." Oncotarget 8.5 (2017): 7852.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ALK-TPM3 rearrangement in adult renal cell carcinoma: a case report and literature review. | Yang J | Diagnostic pathology | 2019 | PMID: 31627758 |
| The pivotal role of sampling recurrent tumors in the precision care of patients with tumors of the central nervous system. | Wong D | Cold Spring Harbor molecular case studies | 2019 | PMID: 31371350 |
Text-mined citations for rs2001675 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.