Submissions for variant NM_000059.4(BRCA2):c.9271G>A (p.Val3091Ile)

gnomAD frequency: 0.00003  dbSNP: rs80359194

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167774	SCV000073785	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000985621	SCV000210685	likely benign	not provided	2020-08-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23328489, 24323938, 32438681, 31131967, 30287823, 28726806, 24916970, 25525159, 21671020, 27376475, 26681674, 25583476, 22970155, 29884841)
Ambry Genetics	RCV000165867	SCV000216616	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	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.
Counsyl	RCV000083157	SCV000489188	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045772	SCV000695230	uncertain significance	not specified	2020-07-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9271G>A (p.Val3091Ile) results in a conservative amino acid change located in the OB3 fold (IPR015188) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250418 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9271G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, gastric adenocarcinoma and pancreatic cancer (Balia_2011, Kwong_2012, Schenkel_2016, Chen_2015, Peixoto_2014, Dudley_2018, Santonocito_2020), however it was also found in controls (Momozawa_2018, Ko_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Two functional studies from the same group utilizing homologous recombination assays to evaluate an impact on protein function, provided conflicting results about the variant (Spugnesi_2013, Balia_2011). However, a more recent study utilizing a cell-based homology directed DNA repair activity assay, with an estimated high sensitivity and specificity, determined the variant to be neutral (i.e. not deleterious) (Hart_2019). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (i.e. 3 calling it VUS, 3 as likely benign, and 1 as benign). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000165867	SCV000911042	benign	Hereditary cancer-predisposing syndrome	2017-01-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985621	SCV001133972	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	The BRCA2 c.9271G>A (p.Val3091Ile) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32438681 (2020), 27376475 (2016), 24916970 (2015), 22970155 (2012), 21671020 (2011)), pancreatic cancer (PMID: 29360161 (2018)), gastric cancer (PMID: 25583476 (2015)), and ampullary cancer (PMID: 26681674 (2016)). This variant has also been observed in numerous reportedly healthy individuals (PMIDs: 30287823 (2018), 31396961 (2020), 32467295 (2020), 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Experimental studies indicate this variant has neutral effects on DNA recombination and homology-directed repair activities (PMIDs: 23328489 (2013), 29884841 (2019), 37731132 (2023)). The frequency of this variant in the general population, 0.000004 (1/250418 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000083157	SCV001139254	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000083157	SCV002512319	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2021-06-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 moderate
All of Us Research Program, National Institutes of Health	RCV004803935	SCV004846147	benign	BRCA2-related cancer predisposition	2024-07-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083157	SCV000115231	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083157	SCV000147595	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045772	SCV000587994	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research