Submissions for variant NM_007294.4(BRCA1):c.3433G>T (p.Val1145Phe)

dbSNP: rs431825396

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000199171	SCV000254974	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-16	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. 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. ClinVar contains an entry for this variant (Variation ID: 96912). This missense change has been observed in individual(s) with a personal or family history of breast cancer and/or ovarian cancer (PMID: 28477318, 29021639). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1145 of the BRCA1 protein (p.Val1145Phe).
Color Diagnostics, LLC DBA Color Health	RCV000579595	SCV000683106	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 1145 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with breast and/or ovarian cancer (PMID: 28477318, 29021639). In a large breast cancer case-control study, this variant has been observed in 1/60466 cases and 1/53461 unaffected controls (OR=0.884; 95%CI 0.055 to 14.136; p-value=1; Leiden Open Variation Database DB-ID BRCA1_004649) (PMID 33471991). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290658	SCV001478786	uncertain significance	not specified	2021-01-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3433G>T (p.Val1145Phe) 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 251182 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3433G>T has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Briceno-Balcazar_2017, Gabaldo_2017). These reports 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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001357066	SCV001983803	uncertain significance	not provided	2021-10-14	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer (Briceo-Balczar 2017, Gabald Barrios 2017); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3552G>T; This variant is associated with the following publications: (PMID: 28477318, 29021639)
Ambry Genetics	RCV000579595	SCV002614529	uncertain significance	Hereditary cancer-predisposing syndrome	2016-10-05	criteria provided, single submitter	clinical testing	The p.V1145F variant (also known as c.3433G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3433. The valine at codon 1145 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is poorly 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	RCV000579595	SCV003848634	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).
Sharing Clinical Reports Project (SCRP)	RCV000083033	SCV000115107	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357066	SCV001552400	uncertain significance	not provided		no assertion criteria provided	clinical testing