Submissions for variant NM_007294.4(BRCA1):c.922A>G (p.Ser308Gly)

dbSNP: rs55767801

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766450	SCV000567142	uncertain significance	not provided	2015-07-02	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.922A>G at the cDNA level, p.Ser308Gly (S308G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). Using alternate nomenclature, this variant would be defined as BRCA1 1041A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser308Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser308Gly occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in in a SWI/SNF binding domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser308Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481247	SCV000600446	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580929	SCV000683377	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 308 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported ambivalent results for this variant on BRCA1 function in the rescue of proliferation, cisplatin sensitivity and embryoid body formation in Brca1-deficient mouse ES cells (PMID: 19770520, 23867111). This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637630	SCV000759097	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 308 of the BRCA1 protein (p.Ser308Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 419382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Ambry Genetics	RCV000580929	SCV001180340	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.S308G variant (also known as c.922A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 922. The serine at codon 308 is replaced by glycine, an amino acid with similar properties. This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics	RCV002481506	SCV002793703	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-07-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000580929	SCV003846290	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).