Submissions for variant NM_007294.4(BRCA1):c.1771A>G (p.Ile591Val)

dbSNP: rs1064795358

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766775	SCV000571084	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1890A>G; This variant is associated with the following publications: (PMID: 15343273)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000482260	SCV000916705	uncertain significance	not specified	2019-03-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1771A>G (p.Ile591Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245912 control chromosomes (gnomAD). 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.1771A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
Invitae	RCV000821605	SCV000962370	benign	Hereditary breast ovarian cancer syndrome	2023-10-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766775	SCV001133499	uncertain significance	not provided	2019-02-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001013057	SCV001173594	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The p.I591V variant (also known as c.1771A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1771. The isoleucine at codon 591 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001013057	SCV003849746	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).
Color Diagnostics, LLC DBA Color Health	RCV001013057	SCV004361050	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 591 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, protein functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251084 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353541	SCV000591350	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ile591Val variant was not identified in the literature nor was it identified in the in dbSNP, Clinvitae database, Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database,COSMIC, the ClinVar database, GeneInsight COGR database, the BIC database, UMD, or Fanconi Anemia (LOVD) databases. The p.Ile591 residue is not conserved in mammals, the variant amino acid Valine (Val) is present in mice and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, 4 out of 5 predict an altered 5' splice site in this region and we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.