Submissions for variant NM_000059.4(BRCA2):c.6739A>G (p.Ser2247Gly)

gnomAD frequency: 0.00004  dbSNP: rs80358896

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079936	SCV000073047	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000587555	SCV000210633	likely benign	not provided	2020-05-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15983021, 25348012, 19491284, 19471317, 22476429, 24817641, 9400938)
Ambry Genetics	RCV000163090	SCV000213595	likely benign	Hereditary cancer-predisposing syndrome	2019-02-09	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	RCV000031645	SCV000488677	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045034	SCV000694991	likely benign	not specified	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6739A>G (p.Ser2247Gly) results in a non-conservative amino acid change in 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 2.8e-05 in 251430 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6739A>G has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Mavarki_1997, Haffty_2006, Haffty_2009, Lu_2012, Caux-Montcoutier_2009). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least three co-occurrences with other pathogenic variants have been reported in the BIC database as well as at our laboratory (BRCA1 c.3700_3704delGTAAA, p.Val1234GlnfsX8; BRCA1 c.4524G>A, p.Trp1508*; BRCA1 c.5096G>A, p.Arg1699Gln), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely benign (n=5) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000163090	SCV000911017	benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587555	SCV001470438	uncertain significance	not provided	2022-06-17	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals or families affected with breast cancer (PMIDs: 9400938 (1997), 19491284 (2009), 19471317 (2009), and 33471991 (2021)). The frequency of this variant in the general population, 0.000062 (8/129102 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587555	SCV001472727	uncertain significance	not provided	2020-10-05	criteria provided, single submitter	clinical testing	The BRCA2 c.6739A>G; p.Ser2247Gly variant (rs80358896) is reported in the literature in multiple individuals affected with breast cancer, but often without specific phenotype information or with other unclassified variants in BRCA2 (Caux-Moncoutier 2009, Haffty 2006, Mavraki 1997). This variant is reported in ClinVar (Variation ID: 38063), and is found in the non-Finnish European population with an allele frequency of 0.0062% (8/129102 alleles) in the Genome Aggregation Database. The serine at codon 2247 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.324). Given the lack of clinical and functional data, the significance of the p.Ser2247Gly variant is uncertain at this time. References: Caux-Moncoutier V et al. Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study. Eur J Hum Genet. 2009 Nov;17(11):1471-80. Haffty BG et al. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet. 2006 Feb;43(2):133-7. Mavraki E et al. Germline BRCA2 mutations in men with breast cancer. Br J Cancer. 1997;76(11):1428-31.
Sema4, Sema4	RCV000163090	SCV002536262	likely benign	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163090	SCV003847412	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).
MGZ Medical Genetics Center	RCV003607207	SCV004543910	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS1_SUP
Sharing Clinical Reports Project (SCRP)	RCV000031645	SCV000054252	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031645	SCV000146919	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587555	SCV000778700	likely benign	not provided	2017-02-17	no assertion criteria provided	clinical testing