Submissions for variant NM_007294.4(BRCA1):c.716A>G (p.His239Arg)

gnomAD frequency: 0.00001  dbSNP: rs80357396

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112775	SCV001161506	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000925
GeneDx	RCV001284302	SCV000210084	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Observed in individuals with familial breast cancer, including one family where a deleterious BRCA1 variant was identified in other affected relatives who did not carry BRCA1 p.His239Arg (Dong et al., 1998; Arnold et al., 2002; Meindl et al., 2002); Published functional studies suggest no damaging effect: showed homologous recombination DNA repair activity and resistance to PARP inhibitors similar to wild type (Bouwman et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 835A>G; This variant is associated with the following publications: (PMID: 28277317, 15235020, 9010228, 9760198, 11802209, 12457999, 26206375, 16267036, 29884841, 9926942, 9582019, 9788437, 20215511, 31853058, 32377563, 31131967, 32546644)
Ambry Genetics	RCV000509604	SCV000608209	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.H239R variant (also known as c.716A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 716. The histidine at codon 239 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in one German female with early-onset breast cancer and a family history of early-onset breast cancer; however, her other affected relatives were found to carry a BRCA1 pathogenic mutation (Dong J et al. Hum. Genet. 1998 Aug;103:154-61). This alteration was also reported in 1/989 German breast cancer or breast/ovarian cancer families undergoing BRCA1 gene testing (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). This variant was not detected among a German control cohort of 95 females and 25 males aged over 60 years without a family history of BRCA-associated cancers (Arnold N et al. J. Chromatogr. B Analyt. Technol. Biomed. Lif. 2002 Dec;782:99-104). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000509604	SCV000911781	benign	Hereditary cancer-predisposing syndrome	2016-02-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284302	SCV001470012	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Invitae	RCV001339091	SCV001532811	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212160	SCV002819583	likely benign	not specified	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.716A>G (p.His239Arg) 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 8e-06 in 250078 control chromosomes (gnomAD and Arnold_2002). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.716A>G has been reported in the literature in affected individuals from families suspected of Hereditary Breast And Ovarian Cancer Syndrome without strong evidence (i.e. cosegregation data) for pathogenicity (e.g. Meindl_2002, Judkins_2005), including one case where another BRCA1 variant was identified in the other affected family members (Dong_1998). Thus, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Additionally, assessment by multifactorial likelihood analysis which incorporates research and clinical data, classified the variant as benign (Parsons_2019). Six submitters, including the expert panel ENIGMA, have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: benign (n=2)/likely benign (n=1), VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112775	SCV000145669	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing