ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3750G>C (p.Glu1250Asp) (rs145903082)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130432 SCV000185296 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000159882 SCV000209959 likely benign not specified 2017-02-28 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.
Invitae RCV000555879 SCV000635917 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1250 of the BRCA1 protein (p.Glu1250Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs145903082, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 141786). 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 aspartic acid 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.
Color RCV000130432 SCV000909293 likely benign Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000159882 SCV001360670 uncertain significance not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3750G>C (p.Glu1250Asp) results in a 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 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3750G>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. An internal specimen found the variant to co-occur with a pathogenic BRCA1 exon 17-18 dup, providing supporting evidence for a benign role. Four ClinVar submissions (evaluation after 2014) cite the variant twice as uncertain significance and twice as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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