Submissions for variant NM_000059.4(BRCA2):c.6325G>A (p.Val2109Ile)

gnomAD frequency: 0.00006  dbSNP: rs79456940

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195307	SCV000072926	benign	Hereditary breast ovarian cancer syndrome	2025-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129753	SCV000184560	likely benign	Hereditary cancer-predisposing syndrome	2018-12-04	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	RCV000034454	SCV000210386	likely benign	not provided	2020-03-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11595708, 19491284, 26709275, 27907908, 31131967, 30415210, 15117986, 14647438, 19016756, 27376475, 27124784, 22995991, 18779604, 15168169, 27658390, 28222693, 27997549, 27701467, 29215753, 28111427, 14973102, 28392550, 30725392, 29642553, 31825140, 22703879)
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240685	SCV000265952	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000406166	SCV000383740	likely benign	Fanconi anemia complementation group D1	2019-03-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000113573	SCV000383741	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-03-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034454	SCV000609564	likely benign	not provided	2017-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034454	SCV000694965	likely benign	not provided	2016-12-01	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6325G>A (p.Val2109Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 38/122036 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0038354 (33/8604). This frequency is about 5 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature, mostly of Asian origin, without strong evidence for causality. BIC reports the variant in 2 individuals who also carry pathogenic variants (BRCA1 c.4163_4164insA; BRCA2 c.9076C>T), also supportive of a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, although some classify it as a VUS. Taken together, this variant is classified likley benign.
Counsyl	RCV000113573	SCV000784864	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-18	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677821	SCV000803981	uncertain significance	Malignant tumor of pancreas	2018-05-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129753	SCV000902701	likely benign	Hereditary cancer-predisposing syndrome	2015-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818210	SCV002068682	likely benign	not specified	2019-03-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129753	SCV002536225	likely benign	Hereditary cancer-predisposing syndrome	2021-05-01	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129753	SCV003852432	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818210	SCV004027456	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034454	SCV000043221	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113573	SCV000146827	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113573	SCV000297542	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353658	SCV000592044	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val2109Ile variant was identified in 7 of 1460 proband chromosomes from Asian individuals with breast or ovarian cancer, and was absent in 520 control chromosomes from healthy individuals (Choi 2004, Haffty 2009, Hu 2004, Kawahara 2004, Sekine 2001, Sugano 2008). The variant was also identified in HGMD, UMD (1X as an unclassified variant), and the BIC database (8X with unknown clinical importance). The variant is listed in dbSNP (ID: rs79456940) “With unknown allele”, with a minor allele frequency of 0.0005 from the 1000 Genomes project, though this frequency is based on only one occurrence of the variant in the tested cohort. The p.Val2109 residue is not conserved in mammals and lower organisms, and the variant amino acid isoleucine (Ile) is present in dog, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein, and Myriad classifies this as a polymorphism (personal communication). In addition, this variant was identified by our laboratory in one individual with a co-occurring pathogenic variant, further increasing the likelihood that this variant may not have clinical importance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250503	SCV002520820	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004541066	SCV004790186	likely benign	BRCA2-related disorder	2023-12-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).