ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5117G>C (p.Gly1706Ala) (rs80356860)

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Total submissions: 20
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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 RCV001086320 SCV000076814 benign Hereditary breast and ovarian cancer syndrome 2020-11-27 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 RCV000586262 SCV000209984 likely benign not provided 2020-10-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17305420, 15689452, 20378548, 24916970, 21990134, 15923272, 30209399, 23683081, 12955716, 12601471, 23469205, 21702907, 21447777, 23479189, 23289006, 25782689, 15235020, 23867111, 25814778, 27495310, 26997744, 18645608, 20516115, 30145549, 30263132, 28781887, 30765603, 33087888)
Ambry Genetics RCV000162991 SCV000213479 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000048801 SCV000336439 likely benign not specified 2015-10-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162991 SCV000683254 likely benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, 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 benign not provided 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000077598 SCV001140486 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001664012 SCV001878732 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353853 SCV000591582 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Gly1706Ala variant has been reported in the literature in 11/1788 proband chromosomes from individuals with hereditary breast and ovarian cancer (Abkevich 2004, Bonatti 2006, Campos 2003, Filippini 2007, Hondow 2011, Lee 2010, Lovelock 2006, Mirkovic 2004, Phelan 2005, Williams 2003) and was not identified in 1100 control chromosomes from healthy individuals (Campos 2003, Phelan 2005). The variant was also identified in dbSNP (ID: rs80356860) with a minor allele frequency of 0.0002 (1000 Genomes Project), LOVD, the ClinVar database (classified as a Likely Benign variant by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (6X with unknown clinical importance), and UMD (28X as a UV variant). The variant was also identified by the Exome Variant Server project in 1 of 8600 European American alleles (frequency: 0.0001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.In the UMD database, this variant has been identified in three individuals with a second pathogenic BRCA1 and BRCA2 variants (c.3049G>T (p.Glu1017X) ; c.IVS2+2T>C (c.67+2T>C), thereby increasing the likelihood that this variant does not have clinical significance. The p.Gly1706 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly1706 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In addition, several functional assays that examined the variant's protein stability, transcriptional transactivation, and subcellular localization predict this variant to be nonpathogenic (Lee 2010, Lovelock 2006, Williams 2003). In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.
Brotman Baty Institute,University of Washington RCV000077598 SCV001243571 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000048801 SCV001906431 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000048801 SCV001959794 benign not specified no assertion criteria provided clinical testing

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