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

gnomAD frequency: 0.00005  dbSNP: rs80356860

Total submissions: 23

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, susceptibility to, 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 ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000077598	SCV000154029	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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.
Eurofins Ntd Llc (ga)	RCV000048801	SCV000336439	likely benign	not specified	2015-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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, susceptibility to, 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, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001086320	SCV002515225	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162991	SCV002537812	likely benign	Hereditary cancer-predisposing syndrome	2021-01-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048801	SCV004026754	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077598	SCV000109401	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077598	SCV000145319	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077598	SCV000207337	benign	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000048801	SCV001959794	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000048801	SCV002036606	benign	not specified		no assertion criteria provided	clinical testing