Submissions for variant NM_007294.4(BRCA1):c.2447A>G (p.His816Arg)

gnomAD frequency: 0.00003  dbSNP: rs80357108

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086517	SCV000075856	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131563	SCV000186567	benign	Hereditary cancer-predisposing syndrome	2014-07-29	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031051	SCV000267701	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031051	SCV000488856	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-07-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001356358	SCV000515981	likely benign	not provided	2018-07-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10882858, 21156238, 15235020, 16267036, 15385441, 25682074)
Color Diagnostics, LLC DBA Color Health	RCV000131563	SCV000910949	benign	Hereditary cancer-predisposing syndrome	2016-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000437338	SCV001338409	likely benign	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2447A>G (p.His816Arg) 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 residue affected by this variant, p.His816, does not lie in a known functional domain/region such as RING-finger and BRCT domain (via InterPro). Missense changes around this codon such as p.Gln804His, p.Asn810Tyr, p.Lys820Glu, p.Thr826Lys that have been evaluated as benign/likely benign by our laboratory, suggesting that considerable number of missense changes may be tolerated in this region. Abkevich_2004 used the combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment and categorized p.His816Arg as one of the unclassified variants in BRCA1 that they find likely to be neutral or of little clinical significance. A report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant allele was found at a frequency of 2.4e-05 in 250756 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2447A>G has been reported in the literature in individuals affected with breast or ovarian cancer (e.g. Klemp_2000, Judkins_2005, Manguoglu_2010, Wong-Brown_2015, Fanale_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 3/53461 controls (Dorling_2021, reported through LOVD). At least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA2 c.658_659delGT, p.Val220IlefsX4), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 15385441, 15235020, 12531920, 15001988, 10882858, 21156238, 25682074, 31112341, 31294896, 31897316, 33471991, 34178674). ClinVar contains an entry for this variant (Variation ID: 37470). Based on the evidence outlined above, the variant was classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000437338	SCV001423023	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.His816Arg variant in BRCA1 has been reported in at least 3 individuals, including 1 Turkish individual, with breast cancer or undergoing genetic testing for breast cancer risk (PMID: 21156238, 10882858, 15235020), but has been identified in 0.006155% (1/16246) of African chromosomes and 0.004414% (5/113268) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80357108). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease also present in the general population. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS, likely benign, and benign variant in ClinVar (Variation ID: 37470). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Histidine (His) at position 816 is not highly conserved in mammals and evolutionary distant species, and 3 species (rabbit, bat, shrew) carry an Arginine (Arg), raising the possibility that this change at this position may be tolerated. One additional variant, resulting in a different amino acid change at the same position, p.His816Leu, has been reported as a VUS in association with disease in ClinVar (Variation ID: 496357). In summary, the clinical significance of the p.His816Arg variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting (Richards 2015).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798027	SCV002043432	uncertain significance	Breast and/or ovarian cancer	2020-06-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131563	SCV002538124	likely benign	Hereditary cancer-predisposing syndrome	2021-07-04	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001356358	SCV003800406	uncertain significance	not provided	2022-03-08	criteria provided, single submitter	clinical testing	The BRCA1 c.2447A>G; p.His816Arg variant (rs80357108) is reported in the literature in individuals with breast cancer (Brown 2019, Manguoglu 2010, Wong-Brown 2015); however, the variant was not determined to be causative. A multifactorial likelihood analysis suggests this variant is likely benign based on co-segregation with disease, family history, and co-occurrence with other pathogenic variants (Parsons 2019). This variant is also reported in ClinVar (Variation ID: 37470). It is found in the general population with an overall allele frequency of 0.002% (6/250656 alleles) in the Genome Aggregation Database. The histidine at codon 816 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.487). Based on available information, the clinical significance of this variant is uncertain at this time. References: Brown A et al. Determination of Pathogenicity of Breast Cancer 1 Gene Variants using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines. Sultan Qaboos Univ Med J. 2019 Nov;19(4):e324-e334. PMID: 31897316. Manguoglu E et al. Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients. Cancer Genet Cytogenet. 2010 Dec;203(2):230-7. PMID: 21156238. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. PMID: 31131967. Wong-Brown MW et al. Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat. 2015 Feb;150(1):71-80. PMID: 25682074.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131563	SCV003847661	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).
PreventionGenetics, part of Exact Sciences	RCV004554620	SCV004117207	uncertain significance	BRCA1-related disorder	2023-02-16	criteria provided, single submitter	clinical testing	The BRCA1 c.2447A>G variant is predicted to result in the amino acid substitution p.His816Arg. This variant has been reported in individuals with breast cancer; however, no further evidence of pathogenicity was provided (Klemp et al. 2000. PubMed ID: 10882858; Manguoğlu et al. 2010. PubMed ID: 21156238; Table S2, Wong-Brown et al. 2015. PubMed ID: 25682074). Using multiple sequence alignment and a measure of chemical differences in amino acids, this variant was indicated to be neutral or have no clinical significance (Abkevich et al. 2004. PubMed ID: 15235020). This variant has been observed in only 6 out of 250,656 alleles in a large population database (http://gnomad.broadinstitute.org/variant/17-41245101-T-C), and has been reported in ClinVar with conflicting interpretations ranging from benign to variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37470/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000031051	SCV000053645	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-11-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031051	SCV000144439	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-04-12	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131563	SCV000787897	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356358	SCV001551504	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.His816Arg variant was identified in the literature but the frequency in an affected population was not provided (Abkevich 2004). The variant was also identified in dbSNP (ID: rs80357108) as "With Uncertain significance, other allele", ClinVar (classified as benign by Ambry Genetics and Sharing Clinical Reports Project; as likely benign by Invitae, GeneDx and two other submitters; and as uncertain significance by three submitters), and in LOVD 3.0 (2x). The variant was not identified in UMD-LSDB. The variant was identified in 6 of 245404 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15298 chromosomes (freq: 0.00007) and European in 5 of 111174 chromosomes (freq: 0.00005), but not in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His816 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.