Submissions for variant NM_007294.4(BRCA1):c.97G>C (p.Glu33Gln)

dbSNP: rs80357066

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049208	SCV000077221	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-15	criteria provided, single submitter	clinical testing	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55769). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 33 of the BRCA1 protein (p.Glu33Gln).
GeneDx	RCV000478523	SCV000572202	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients referred for BRCA1/2 testing (Judkins et al., 2005); Also known as 216G>C; This variant is associated with the following publications: (PMID: 21147198, 10923033, 8944023, 16267036, 20104584, 24389207, 30209399)
Color Diagnostics, LLC DBA Color Health	RCV000775196	SCV000909422	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 33 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 functions in a haploid cell proliferation assay and in a E3 ligase and a yeast two-hybrid BARD1 binding assays (PMID: 25823446, 30209399). A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.0673 and 0.5995 based on co-occurrence and family history, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281896	SCV002571760	uncertain significance	not specified	2022-08-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.97G>C (p.Glu33Gln) results in a conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250748 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.97G>C has been reported in the literature in a patient cohort referred to testing for Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been reported in our lab (CHEK2 c.1283C>T, p.Ser428Phe), providing supporting evidence for a benign role. Two independent publications report experimental evidence evaluating the impact of the variant on protein function: Starita_2015 classified the variant as VUS after assaying for E3 ligase activity and BARD1 binding affinity, and Findlay_2018 classified the variant as functional after employing a haploid cell survival assay. Three ClinVar submitters have assessed the variant since 2014: all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000775196	SCV002693512	likely benign	Hereditary cancer-predisposing syndrome	2021-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111754	SCV000144281	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353807	SCV000591238	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu33Gln variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs80357066) as “With Uncertain significance allele”, ClinVar (as uncertain significance by BIC, COGR, GeneDx, and Invitae), Clinvitae (3x as uncertain signifiance), and BIC Database (1x as "unknown"). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017).. The p.Glu33Gln residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735483	SCV000863620	uncertain significance	Breast and/or ovarian cancer	2014-01-22	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111754	SCV001242824	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro