Submissions for variant NM_000059.4(BRCA2):c.8687G>A (p.Arg2896His)

gnomAD frequency: 0.00002  dbSNP: rs80359128

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086184	SCV000073615	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129089	SCV000183797	likely benign	Hereditary cancer-predisposing syndrome	2018-12-31	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	RCV000077448	SCV000488098	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000034466	SCV000516569	likely benign	not provided	2021-04-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 19043619, 24817641, 22476429, 25348012, 31131967)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418186	SCV000695173	likely benign	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8687G>A (p.Arg2896His) results in a non-conservative amino acid change located in the tower domain within the OB2 fold (Karchin_2008) in the DNA binding region 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 2e-05 in 252456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8687G>A has been reported in the literature in individuals affected with a personal and/or family history of breast and/or ovarian cancer (e.g. Lu_2012, Farra_2019, Salmi_2021), but was found also in healthy controls (e.g. Johnston_2012, and in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had a similar activity to the wild type in a homology-directed repair assay (Karchin_2008). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=4), likely benign (n=4) or benign (n=1). Based on the evidence outlined above, the variant was re-classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000129089	SCV000902894	benign	Hereditary cancer-predisposing syndrome	2016-11-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034466	SCV001133944	likely benign	not provided	2019-05-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034466	SCV001746179	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000077448	SCV002525975	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-10	criteria provided, single submitter	clinical testing	The BRCA2 c.8687G>A (p.Arg2896His) missense change has a maximum frequency of 0.006152% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32950861-G-A?dataset=gnomad_r2_1). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in 1 woman older than 70 years of age who have never had cancer (https://whi.color.com/variant/13-32950861-G-A). This variant was reported in an individual with prostate cancer (PMID: 34242281). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4	RCV000129089	SCV002531968	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	curation
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034466	SCV000043232	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000077448	SCV000109246	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-12-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077448	SCV000147439	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353522	SCV000592222	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg2896His variant is listed 3 times in the BIC database. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80359128) but no frequency information was provided, and so the frequency in the general population is not known. The p.Arg289 residue is not highly conserved in mammals and the variant amino acid histidine (His) is present in rat, mouse and chicken, increasing the likelihood this variant does not have important functional or clinical signficance. In addition, computational analyses (SIFT, PolyPhen2, and AlignGVGD) do not suggest a high likelihood of impact to the protein, but this information is not predictive enough to rule out pathogenicity. In addition, one in-silico study reported this variant as neutral (Karchin 2008). In summary, based on the current information presented above, this variant is predicted benign.