ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1802A>G (p.His601Arg) (rs371631805)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168128 SCV000218786 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-23 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 601 of the BRCA1 protein (p.His601Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs371631805, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer (PMID: 15726418). This variant has also been reported as 1921A>G. ClinVar contains an entry for this variant (Variation ID: 188204). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000220587 SCV000273305 likely benign Hereditary cancer-predisposing syndrome 2019-04-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000587213 SCV000698887 uncertain significance not provided 2016-08-28 criteria provided, single submitter clinical testing Variant Summary: The BRCA1 c.1802A>G (p.His601Arg) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large and broad control population from ExAC with an allele frequency of 2/121060 (1/60,530), which does not exceed the maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. It was only observed in African sub-population with allele frequency of 2/10252. The variant of interest has been reported by a publication that found the variant in 3 unaffected African American sisters and was not present in their 2 affected sisters with Breast Cancer (McKean-Cowdin_2005), an evidence for lack of cosegregation, suggesting the variant to be a rare polymorphism in populations of African orgin. Multiple clinical laboratories cite the variant as "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "VUS-possibly benign," until additional information becomes available.
Counsyl RCV000663081 SCV000786164 uncertain significance Breast-ovarian cancer, familial 1 2018-03-12 criteria provided, single submitter clinical testing
Color RCV000220587 SCV001346477 likely benign Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing

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