Submissions for variant NM_007294.4(BRCA1):c.683T>A (p.Phe228Tyr)

dbSNP: rs191872612

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166112	SCV000216881	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-25	criteria provided, single submitter	clinical testing	The p.F228Y variant (also known as c.683T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 683. The phenylalanine at codon 228 is replaced by tyrosine, an amino acid with highly similar properties. 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.
Genetic Services Laboratory, University of Chicago	RCV000503325	SCV000593686	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000503325	SCV000699292	uncertain significance	not specified	2021-01-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.683T>A (p.Phe228Tyr) results in a 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 4.1e-06 in 246068 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.683T>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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	RCV001042814	SCV001206519	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-02	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: 186506). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs191872612, gnomAD 0.007%). This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 228 of the BRCA1 protein (p.Phe228Tyr).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166112	SCV003848013	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).