Submissions for variant NM_007294.4(BRCA1):c.548G>T (p.Gly183Val)

dbSNP: rs1555594081

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509974	SCV000607982	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-30	criteria provided, single submitter	clinical testing	The p.G183V variant (also known as c.548G>T) is located in coding exon 7 of the BRCA1 gene. The glycine at codon 183 is replaced by valine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 7. This alteration has been reported as a variant of unknown significance in a cohort of 67 patients with unilateral hormone-dependent breast cancer and positive family history (Concolino P et al. Int J Mol Sci, 2019 Jul;20:). RNA studies have demonstrated that this alteration results in an increase in the expression of BRCA1 alternate isoforms involving coding exons 7 and 8 (Ambry internal data). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000509974	SCV000688638	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125056	SCV001284091	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001865673	SCV002289846	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-06-17	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with breast cancer (PMID: 31336956). ClinVar contains an entry for this variant (Variation ID: 441376). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 183 of the BRCA1 protein (p.Gly183Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001125056	SCV004047789	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant c.548G>T (p.Gly183Val) in BRCA1 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS). The p.Gly183Val variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Gly at position 183 is changed to a Val changing protein sequence and it might alter its composition and physio-chemical properties. The amino acid change p.Gly183Val in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479147	SCV004222968	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.548G>T (p.Gly183Val) 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 was absent in 250814 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.548G>T has been reported in the literature in at-least one female individual affected with Unilateral Breast, whose father was also a carrier and was diagnosed with Breast Cancer at age of 78 years-old (example, Concolino_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31336956). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.