ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5117G>C (p.Gly1706Ala) (rs80356860)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077598 SCV000244384 benign Breast-ovarian cancer, familial 1 2015-08-10 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 = 0.0000495
Invitae RCV000586262 SCV000076814 benign not provided 2019-02-12 criteria provided, single submitter clinical testing
Counsyl RCV000077598 SCV000154029 likely benign Breast-ovarian cancer, familial 1 2014-03-23 criteria provided, single submitter literature only
GeneDx RCV000048801 SCV000209984 likely benign not specified 2018-03-07 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.
Ambry Genetics RCV000162991 SCV000213479 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000048801 SCV000336439 likely benign not specified 2015-10-13 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048801 SCV000591582 likely benign not specified 2014-10-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048801 SCV000605904 likely benign not specified 2017-01-16 criteria provided, single submitter clinical testing
Color RCV000162991 SCV000683254 likely benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586262 SCV000699204 benign not provided 2016-03-30 criteria provided, single submitter clinical testing Variant Summary: The BRCA1 c.5117G>C variant involves the alteration of a conserved nucleotide, resulting in an amino acid change from a Gly to an Ala at codon 1706. G1706 is a highly conserved residue located at the interface between the two BRCT domains, which forms the binding pocket for the peptide and functional studies have shown G1706A may be mildly destablizing (Lee_CR_2010); however, this finding was in contrast to Lovelock et al 2006, showing no change in stability. Regardless, the implications of this possible reduction in protein stability in cancer are not known. 4/5 in-silico tools predict a pathogenic outcome. Contrary to in silico and the conflicting stability assay results, multiple other functional assays from independent labs show the variant to have similar activity compared to WT, including, subcellular localization, transcriptional transactivation, centrosome amplification, binding activity, as well as splicing/transcription analysis via patient mRNA (Lovelock_2006, Campos_2003, Lee_CR_2010).The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.004% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.10%). The variant has been reported in the literature in affected individuals, without strong evidence for causality (i.e. co-segregation with disease). The variant has been reported in databases and publications to co-occur in patients with pathogenic variants including 3 patients who also carry BRCA1 c.3049G>T (p.Glu1017X; UMD), 1 patient with BRCA2 c.IVS2+2T>C (c.67+2T>C; UMD), 1 patient with BRCA2 c.51_52delAC (p.Arg18LeufsX12; UMD) and 1 patient with BRCA1 c.5263insC (p.Gln1756fs; Carraro_2013). Additionally, the variant was reported to not segregate with disease in multiple pedigrees, including one family with one affected individual without the variant as well as a second family with two unaffected variant carriers (ages 70 and 90; Lovelock_2006). In another family, the affected proband was positive for the variant, but the variant was not inherited from the cancer affected maternal side of the family (fathers side had no cancer history; Lovelock_2006). Furthermore, multiple reputable clinical labs have classified the variant as likely benign/benign. Therefore, due to the lack of co-segregation of the variant with disease, the co-occurrence of the variant with pathogenic variants in multiple patients, and functional assays showing similar activity to WT BRCA1, this variant has been classified as a benign variant.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077598 SCV000744599 benign Breast-ovarian cancer, familial 1 2017-05-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586262 SCV000887715 likely benign not provided 2017-01-16 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077598 SCV000109401 likely benign Breast-ovarian cancer, familial 1 2012-08-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077598 SCV000145319 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000077598 SCV000207337 benign Breast-ovarian cancer, familial 1 2014-11-06 no assertion criteria provided clinical testing
Department of Medical Genetics,University Hospital of North Norway RCV000077598 SCV000301437 likely benign Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing

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