ClinVar Miner

Submissions for variant NM_007300.4(BRCA1):c.2447A>G (p.His816Arg) (rs80357108)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047843 SCV000075856 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131563 SCV000186567 benign Hereditary cancer-predisposing syndrome 2014-07-29 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031051 SCV000267701 likely benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000031051 SCV000488856 uncertain significance Breast-ovarian cancer, familial 1 2016-07-06 criteria provided, single submitter clinical testing
GeneDx RCV000437338 SCV000515981 likely benign not specified 2017-02-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000588248 SCV000698953 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2447A>G (p.His816Arg) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a neutral outcome (meets BP4 ACMG guideline). 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.Lys820Glyp.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 classified p.His816Arg as one of the unclassified variants in BRCA1 that they find likely to be neutral or of little clinical significance. The variant was observed in the large, broad control population, ExAC, with an allele frequency of allele frequency of 0.0008% (1/121356 chromosomes), which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.10%). The variant has been reported in affected individuals in literature and in individuals undergoing BRCA1/2 testing by clinical databases/labs, without a strong evidence for causality. Multiple clinical labs have classified the variant as benign (without evidence to independently evaluate), and BIC reports the variant to co-occur with a truncating BRCA2 variant (c.658_659delGT, p.Val220Ilefs) (meets BP5 ACMG guideline), suggesting the benign nature of the variant. Although this variant meets the criteria for classification as "Likely Benign" based solely upon application of the ACMG guidelines, additional information about cosegregation and in-vitro/in-vivo studies demonstrating the functional impact of this variant have not been reported. Taken together, this variant has currently been classified as a "Variant of Uncertain Significance - Possibly Benign."
Color RCV000131563 SCV000910949 benign Hereditary cancer-predisposing syndrome 2016-12-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031051 SCV000053645 benign Breast-ovarian cancer, familial 1 2009-11-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031051 SCV000144439 uncertain significance Breast-ovarian cancer, familial 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

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