VCV000051411.10 - ClinVar

NM_000059.4(BRCA2):c.316+6T>C

Germline

Classification

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.

(6)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.316+6T>C

Variation ID: 51411 Accession: VCV000051411.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32319331 (GRCh38) [ NCBI UCSC ] 13: 32893468 (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	Apr 1, 2014	Feb 14, 2024	Oct 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.316+6T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000013.11:g.32319331T>C
NC_000013.10:g.32893468T>C
NG_012772.3:g.8852T>C
NG_017006.2:g.1033A>G
LRG_293:g.8852T>C
LRG_293t1:c.316+6T>C
U43746.1:n.544+6T>C

... more HGVS ... less HGVS

Protein change

Other names

IVS3+6T>C

Canonical SPDI

NC_000013.11:32319330:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

Breast Cancer Information Core (BIC) (BRCA2): 544+6&base_change=T to C ClinGen: CA017400 dbSNP: rs81002900 VarSome

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
Gene	OMIM	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.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18972	19131

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.
Breast-ovarian cancer, familial, susceptibility to, 2	Uncertain significance (1)	no assertion criteria provided	Dec 23, 2003	RCV000113398.2
Hereditary breast ovarian cancer syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 13, 2023	RCV001366247.5
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 12, 2023	RCV003362678.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Feb 19, 2021	RCV001800338.1
Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2021	RCV003473325.1

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.
Uncertain significance (Feb 19, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002046667.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Publications: PubMed (1) PubMed: 30883759
Uncertain significance (Nov 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212879.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Jul 12, 2023)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004063121.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Publications: PubMed (1) PubMed: 30883759 Comment: The c.316+6T>C intronic variant results from a T to C substitution 6 nucleotides after coding exon 2 in the BRCA2 gene. This nucleotide position is … (more) The c.316+6T>C intronic variant results from a T to C substitution 6 nucleotides after coding exon 2 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have shown this alteration to result in the skipping of coding exon 2 (Ambry internal data; Fraile-Bethencourt E et al. J Pathol, 2019 Aug;248:409-420). Coding exon 2 is sometimes referred to as exon 3 in the literature. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Oct 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001562544.4 First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 21120943‚ 17576681‚ 9536098‚ 30883759‚ 32641407 Comment: This sequence change falls in intron 3 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. … (more) This sequence change falls in intron 3 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs81002900, gnomAD 0.0009%). This variant has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 51411). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 30883759, 32641407; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Aug 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004361161.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 21120943‚ 30883759‚ 32641407 Comment: This variant causes a T to C nucleotide substitution at the +6 position of intron 3 of the BRCA2 gene. RNA studies using patient-derived cells … (more) This variant causes a T to C nucleotide substitution at the +6 position of intron 3 of the BRCA2 gene. RNA studies using patient-derived cells and minigene splicing assays have shown that this variant causes skipping of exon 3, but does not completely abolish normal RNA splicing (PMID: 30883759, 32641407). Functional studies have shown this variant can complement loss of BRCA2 in mouse embryonic stem cells and mouse embryonic stem cells expressing this variant are not hypersensitive to DNA-damaging agents (PMID: 32641407). This variant has been reported in an individual with a personal and/or family history of breast or ovarian cancer (PMID: 21120943). This variant has been identified in 1/248932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 23, 2003)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000146566.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Number of individuals with the variant: 1 Ethnicity/Population group: Western European

Comment:

The c.316+6T>C intronic variant results from a T to C substitution 6 nucleotides after coding exon 2 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have shown this alteration to result in the skipping of coding exon 2 (Ambry internal data; Fraile-Bethencourt E et al. J Pathol, 2019 Aug;248:409-420). Coding exon 2 is sometimes referred to as exon 3 in the literature. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change falls in intron 3 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs81002900, gnomAD 0.0009%). This variant has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 51411). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 30883759, 32641407; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This variant causes a T to C nucleotide substitution at the +6 position of intron 3 of the BRCA2 gene. RNA studies using patient-derived cells and minigene splicing assays have shown that this variant causes skipping of exon 3, but does not completely abolish normal RNA splicing (PMID: 30883759, 32641407). Functional studies have shown this variant can complement loss of BRCA2 in mouse embryonic stem cells and mouse embryonic stem cells expressing this variant are not hypersensitive to DNA-damaging agents (PMID: 32641407). This variant has been reported in an individual with a personal and/or family history of breast or ovarian cancer (PMID: 21120943). This variant has been identified in 1/248932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System.	Tubeuf H	Cancer research	2020	PMID: 32641407
Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.	Fraile-Bethencourt E	The Journal of pathology	2019	PMID: 30883759
EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients.	Caux-Moncoutier V	Human mutation	2011	PMID: 21120943
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs81002900 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.316+6T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs81002900 ...