Submissions for variant NM_007294.4(BRCA1):c.212G>T (p.Arg71Met)

dbSNP: rs80356913

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165177	SCV000215889	likely pathogenic	Hereditary cancer-predisposing syndrome	2014-07-15	criteria provided, single submitter	clinical testing	The c.212G>T variant (also known as p.R71M), located in coding exon 3 of the BRCA1 gene, results from a G to T substitution at nucleotide position 212. This change occurs in the last base pair of coding exon 3 which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the arginine at codon 71 to methionine, an amino acid with similar properties. <span style="background-color:initial">Two disease-causing mutations, p.R71G and p.R71K, have been described at the same codon <span style="background-color:initial">(Janavi&egrave;ius R. EPMA J. 2010;1(3):397-412;83(4):465-9,Sanz DJ et al. Clin Cancer Res. 2010;16(6):1957-67; Meindl et al. Int J Cancer. 2002;97:472-480)<span style="background-color:initial">.<span style="background-color:initial"> Both the nucleotide and<span style="background-color:initial"> amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native donor splice site; however, direct evidence is unavailable. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico<span style="background-color:initial"> analyses, respectively. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258240	SCV000325251	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001053345	SCV001217603	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-02	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.212G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 11802209, 21863257, 22505045, 23451180, 29752822). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 185705). This variant has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 22984553). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 71 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496554	SCV000587032	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000258240	SCV001242561	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro