Submissions for variant NM_000059.4(BRCA2):c.6938-2A>G

dbSNP: rs81002863

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083132	SCV001161656	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.994607
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083132	SCV000327543	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000479362	SCV000567943	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with prostate cancer (Momozawa et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7166-2A>G; This variant is associated with the following publications: (PMID: 21523855, 31131967, 31214711)
Ambry Genetics	RCV000509741	SCV000608224	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The c.6938-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 12 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779943	SCV000916886	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6938-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing, resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244092 control chromosomes. The c.6938-2A>G variant has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer. This report does not provide unequivocal conclusions about an association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779943	SCV001577441	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033, 21520333, 31214711). ClinVar contains an entry for this variant (Variation ID: 52222). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000083132	SCV004825839	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_006186) and an individual affected with prostate cancer (PMID: 31214711). This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.076 and 5.302, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000083132	SCV000115206	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-01-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083132	SCV000146973	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735592	SCV000863730	likely pathogenic	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing