Submissions for variant NM_007294.4(BRCA1):c.305C>G (p.Ala102Gly)

dbSNP: rs80357190

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566761	SCV004101421	benign	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.305C>G variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 102 (p.Ala102Gly). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.00, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30219179) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.015 (based on Co-occurrence LR=1.177; Family History LR=0.0127), below the threshold for strong benign evidence (LR <0.05) (BP5_Strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP1_Strong, BS3, BP5_Strong).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203639	SCV000076075	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001353922	SCV000209905	likely benign	not provided	2019-06-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18703817, 25814778, 22711857)
Ambry Genetics	RCV000166160	SCV000216934	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The p.A102G variant (also known as c.305C>G), located in coding exon 5 of the BRCA1 gene, results from a C to G substitution at nucleotide position 305. The alanine at codon 102 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic gross deletion in BRCA1 in a hereditary breast and ovarian cancer family (Palma MD et al. Cancer Res. 2008 Sep 1;68(17):7006-14). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048062	SCV000699001	benign	not specified	2021-09-13	criteria provided, single submitter	clinical testing	Variant summary: The variant, BRCA1 c.305C>G (p.Ala102Gly) results in a non-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. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (IARC class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant was absent in 250608 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.305C>G has been reported in the literature in individuals affected with Breast cancer and ovarian cancer (Alsop_2012, Palma_2008). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Recently a large scale multifactorial likelihood quantitative analysis approach based on variant location, bioinformatic prediction of variant effect, cosegregation, family cancer history profile, cooccurrence with a pathogenic variant in the same gene, breast tumor pathology, and casecontrol information has classified this variant as benign (Parsons_2019). At-least one co-occurrence with another pathogenic variants have been reported (BRCA1 Del exons 8-9, Palma_2008 and an unspecified co-occurrence in Alsop_2012), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign (n=1, including the expert panel)/likely benign (n=3). Based on the evidence outlined above, the variant was re-classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000166160	SCV000903872	likely benign	Hereditary cancer-predisposing syndrome	2016-04-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166160	SCV002538180	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000031086	SCV004823674	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-07	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031086	SCV000053682	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031086	SCV000144993	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	RCV001353922	SCV000591258	uncertain significance	not provided		no assertion criteria provided	clinical testing