Submissions for variant NM_007294.4(BRCA1):c.1834A>G (p.Arg612Gly)

dbSNP: rs80357245

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111696	SCV001161490	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 0.000492
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047605	SCV000075618	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000221996	SCV000275535	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	clinical testing	The p.R612G variant (also known as c.1834A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1834. The arginine at codon 612 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000111696	SCV000489573	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000485391	SCV000568878	uncertain significance	not provided	2016-08-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1834A>G at the cDNA level, p.Arg612Gly (R612G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). Using alternate nomenclature, this variant would be defined as BRCA1 1953A>G. This variant was co-observed with a pathogenic BRCA2 variant in an individual with bilateral breast and ovarian cancer (Minucci 2016). BRCA1 Arg612Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Arg612Gly occurs at a position that is not conserved and is located within the NLS2 motif and a region known for interaction with multiple proteins (Borg 2010, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Arg612Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000221996	SCV000688349	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 612 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). A functional study has shown the mutant protein to exhibit normal homology-directed recombination activity (PMID: 2668991). This variant has been reported in an individual affected with breast and ovarian cancer who also carried a pathogenic variant in the BRCA2 gene that could explain the observed phenotype (PMID: 2668991). This variant has been identified in 1/251080 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485391	SCV001133500	uncertain significance	not provided	2021-05-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000111696	SCV004818277	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2022-11-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767044	SCV005381067	likely benign	not specified	2024-08-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1834A>G (p.Arg612Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251080 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1834A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Hovland_2022, Lu_2015), however without strong evidence for causality (e.g., lack of co-segregation data). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Lu_2015). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 34981296, 36833189, 26689913). ClinVar contains an entry for this variant (Variation ID: 54367). Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111696	SCV000144198	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing