NM_000535.7(PMS2):c.2356C>A (p.Leu786Met) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Jun 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000656951.34

Allele description [Variation Report for NM_000535.7(PMS2):c.2356C>A (p.Leu786Met)]

NM_000535.7(PMS2):c.2356C>A (p.Leu786Met)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.2356C>A (p.Leu786Met)

HGVS:

NC_000007.14:g.5977677G>T
NG_008466.1:g.36430C>A
NM_000535.7:c.2356C>AMANE SELECT
NM_001322003.2:c.1951C>A
NM_001322004.2:c.1951C>A
NM_001322005.2:c.1951C>A
NM_001322006.2:c.2200C>A
NM_001322007.2:c.2038C>A
NM_001322008.2:c.2038C>A
NM_001322009.2:c.1984C>A
NM_001322010.2:c.1795C>A
NM_001322011.2:c.1423C>A
NM_001322012.2:c.1423C>A
NM_001322013.2:c.1783C>A
NM_001322014.2:c.2389C>A
NM_001322015.2:c.2047C>A
NP_000526.2:p.Leu786Met
NP_001308932.1:p.Leu651Met
NP_001308933.1:p.Leu651Met
NP_001308934.1:p.Leu651Met
NP_001308935.1:p.Leu734Met
NP_001308936.1:p.Leu680Met
NP_001308937.1:p.Leu680Met
NP_001308938.1:p.Leu662Met
NP_001308939.1:p.Leu599Met
NP_001308940.1:p.Leu475Met
NP_001308941.1:p.Leu475Met
NP_001308942.1:p.Leu595Met
NP_001308943.1:p.Leu797Met
NP_001308944.1:p.Leu683Met
LRG_161t1:c.2356C>A
LRG_161:g.36430C>A
NC_000007.13:g.6017308G>T
NM_000535.5:c.2356C>A
NM_000535.6:c.2356C>A
NM_000535.7:c.2356C>A
NM_001322014.2:c.2389C>A
NR_136154.1:n.2400C>A
p.L786M

Protein change:

L475M

Links:

dbSNP: rs576055272

NCBI 1000 Genomes Browser:

rs576055272

Molecular consequence:

NM_000535.7:c.2356C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1951C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1951C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1951C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.2200C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.2038C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.2038C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1984C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1795C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1423C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1423C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1783C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2389C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.2047C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2400C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279150	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Nov 17, 2017)	germline	clinical testing	Citation Link,
SCV000892766	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Jun 1, 2024)	germline	clinical testing	Citation Link,
SCV001553423	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing
SCV001749923	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV001799766	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001917833	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Details of each submission

From GeneDx, SCV000279150.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is denoted PMS2 c.2356C>A at the cDNA level, p.Leu786Met (L786M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). PMS2 Leu786Met was identified in at least one individual among a cohort of 145 patients who underwent PMS2 clinical testing, as well as in an individual with previously negative BRCA1/2 analysis (Vaughn 2010, Yadav 2016). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Leu786Met is located in the Endonuclease domain (Fukui 2011). In-silico analysis, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Leu786Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000892766.28

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

PMS2: PP2, BS2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The PMS2 p.Leu786Met variant was not identified in the literature nor was it identified in the COGR, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, and the Insight Hereditary Tumors databases. Furthermore, the variant was not identified in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs576055272) as with other allele, in the ClinVar and Clinvitae databases as benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by Ambry Genetics and Prevention Genetics; and as uncertain significance by GeneDx. In addition, the variant was identified in the Cosmic database 1X as pathogenic in a lobular carcinoma and in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002). The variant was further identified in control databases in 287 of 244884 chromosomes (10 homozygous) at a frequency of 0.001 increasing the likelihood that this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15242 chromosomes (freq: 0.00007), Other in 1 of 5466 chromosomes (freq: 0.0002), Latino in 3 of 33562 chromosomes (freq: 0.00009), European Non-Finnish in 15 of 110756 chromosomes (freq: 0.0001), East Asian in 1 of 17174 chromosomes (freq: 0.00006), and South Asian in 266 of 30658 chromosomes (freq: 0.009); it was not observed in the Ashkenazi Jewish and European Finnish, populations. The p.Leu786 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From GenomeConnect - Invitae Patient Insights Network, SCV001749923.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Benign and reported on 04-07-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001799766.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001917833.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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