Submissions for variant NM_000059.4(BRCA2):c.8918G>A (p.Arg2973His)

gnomAD frequency: 0.00004  dbSNP: rs80359143

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082957	SCV000073671	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000128971	SCV000172856	likely benign	Hereditary cancer-predisposing syndrome	2019-04-28	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	RCV000587937	SCV000210676	likely benign	not provided	2020-02-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29884841, 31131967, 30212499, 16284991, 22034289, 19043619, 22711857, 21702907, 20127978, 30287823)
Color Diagnostics, LLC DBA Color Health	RCV000128971	SCV000537482	likely benign	Hereditary cancer-predisposing syndrome	2014-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505714	SCV000695192	likely benign	not specified	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8918G>A (p.Arg2973His) 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 4e-05 in 249436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.8918G>A has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Alsop_2012, Fackenthal_2012, Pal_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A Japanese case-control study reported the variant as "benign" due to its presence in controls and absence in cases (Momozawa_2018). One co-occurrence with another pathogenic variant has been reported (BRCA2 c.1219_1219delC, p.Gln407Argfs, BIC), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on HDR activity (Hart_2019, Richardson_2021). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587937	SCV000887947	likely benign	not provided	2023-02-10	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761134	SCV000891050	uncertain significance	Neuroblastoma	2017-04-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770734	SCV000902215	uncertain significance	Breast and/or ovarian cancer	2016-12-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000031777	SCV001139238	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587937	SCV003800450	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	The BRCA2 c.8918G>A; p.Arg2973His variant (rs80359143) is reported in the literature in individuals affected with breast or ovarian cancer, but without clear disease association (Alsop 2012, Fackenthal 2012, Morgan 2010, Pal 2005). This variant is also reported in ClinVar (Variation ID: 38194), and is found in the general population with an overall allele frequency of 0.0040% (10/249436 alleles) in the Genome Aggregation Database. The arginine at codon 2973 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.449). In vitro functional analyses demonstrate no effect on homology directed repair (Hart 2019, Richardson 2021). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Alsop K et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. PMID: 22711857. Fackenthal JD et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012 Sep 1;131(5):1114-23. PMID: 22034289. Hart SN et al. Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. Genet Med. 2019 Jan;21(1):71-80. PMID: 29884841. Morgan JE et al. Genetic diagnosis of familial breast cancer using clonal sequencing. Hum Mutat. 2010 Apr;31(4):484-91. PMID: 20127978. Pal T et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005 Dec 15;104(12):2807-16. PMID: 16284991. Richardson ME et al. Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. Am J Hum Genet. 2021 Mar 4;108(3):458-468. PMID: 33609447.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000505714	SCV004243072	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031777	SCV004846094	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000031777	SCV004930994	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-04	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Sharing Clinical Reports Project (SCRP)	RCV000031777	SCV000054385	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-11-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031777	SCV000147488	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing