Submissions for variant NM_007294.4(BRCA1):c.2222C>G (p.Ser741Cys)

gnomAD frequency: 0.00001  dbSNP: rs80357051

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214807	SCV000275313	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing	The p.S741C variant (also known as c.2222C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2222. The serine at codon 741 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000767205	SCV000566591	uncertain significance	not provided	2015-05-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2222C>G at the cDNA level, p.Ser741Cys (S741C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 2341C>G. BRCA1 Ser741Cys 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 Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser741Cys occurs at a position that is not conserved and is located within the DNA binding domain (Narod 2004). Published evolutionary conservation analyses predicted that this variant may have an effect on protein function, while in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function (Fleming 2003, Ramirez 2004, Burk-Herrick 2006). Based on currently available information, it is unclear whether BRCA1 Ser741Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486164	SCV000600278	uncertain significance	not specified	2017-04-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000486164	SCV000602735	uncertain significance	not specified	2017-03-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000111801	SCV000784884	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214807	SCV001352953	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 741 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000191). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0331 and 1,6879, respectively (PMID: 31131967). This variant has been identified in 1/251070 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.
Invitae	RCV001299384	SCV001488470	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 741 of the BRCA1 protein (p.Ser741Cys). This variant is present in population databases (rs80357051, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 54506). 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%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000486164	SCV003801051	uncertain significance	not specified	2023-01-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2222C>G (p.Ser741Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2222C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000214807	SCV003847841	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111801	SCV000144346	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing