Submissions for variant NM_000059.4(BRCA2):c.9581C>A (p.Pro3194Gln)

gnomAD frequency: 0.00001  dbSNP: rs28897760

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045860	SCV000073873	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131306	SCV000186278	likely benign	Hereditary cancer-predisposing syndrome	2018-12-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV001719713	SCV000210511	likely benign	not provided	2019-08-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22875147, 23704879, 18724707, 27223485, 21702907, 29116469, 27403073, 32854451)
Counsyl	RCV000031833	SCV000487802	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719713	SCV000600868	uncertain significance	not provided	2024-10-03	criteria provided, single submitter	clinical testing	The BRCA2 c.9581C>A (p.Pro3194Gln) variant has been reported in the published literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 34178674 (2021), 34026625 (2021), 32854451 (2020), 32438681 (2020), 27403073 (2016), 27223485 (2016)), including one individual who also carried a pathogenic BRCA1 variant (PMID:29116469 (2018)). In a large scale breast cancer association study, this variant has been observed in 3 breast cancer cases and 4 reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Functional studies demonstrated that this variant has an inconclusive effect on protein function (PMID: 23704879 (2013)). The frequency of this variant in the general population, 0.000023 (3/129140 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000131306	SCV000689208	likely benign	Hereditary cancer-predisposing syndrome	2017-06-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160173	SCV000917016	benign	not specified	2022-01-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9581C>A (p.Pro3194Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251964 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9581C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Palmero_2015, Brianese_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5266dupC, p.Gln1756Profs*74; BRCA2 c.3978_3979ins4, p.Ala1327fsX4) (BIC database and Brianese_2018), providing supporting evidence for a benign role. A recent case-control study showed that this variant is not associated with breast cancer (Dorling_2021). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Tram_2013). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.
All of Us Research Program, National Institutes of Health	RCV004803096	SCV004846191	likely benign	BRCA2-related cancer predisposition	2024-05-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031833	SCV000054441	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031833	SCV000147668	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532471	SCV004746517	uncertain significance	BRCA2-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The BRCA2 c.9581C>A variant is predicted to result in the amino acid substitution p.Pro3194Gln. This variant is predicted to abolish binding of the CDK2 kinase and creates a new binding site (Tram et al. 2013. PubMed ID: 23704879). This variant was also identified in individuals with a personal and family history of breast cancer and other hereditary cancer syndrome (Table S6, Hondow et al. 2011. PubMed ID: 21702907; Palmero et al. 2016. PubMed ID: 27223485). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38250/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.