Submissions for variant NM_000059.4(BRCA2):c.3655T>G (p.Phe1219Val)

dbSNP: rs80358610

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506626	SCV000600558	uncertain significance	not specified	2017-02-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581561	SCV000688821	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 1219 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal or family history of breast cancer (PMID: 35980532). This variant has been identified in 1/250274 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702274	SCV000831121	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1219 of the BRCA2 protein (p.Phe1219Val). This variant is present in population databases (rs80358610, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 438971). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. 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.
Ambry Genetics	RCV000581561	SCV002617514	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	The p.F1219V variant (also known as c.3655T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 3655. The phenylalanine at codon 1219 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000581561	SCV003846767	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).
All of Us Research Program, National Institutes of Health	RCV004802108	SCV004845194	uncertain significance	BRCA2-related cancer predisposition	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 1219 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal or family history of breast cancer (PMID: 35980532). This variant has been identified in 1/250274 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506626	SCV005421991	uncertain significance	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3655T>G (p.Phe1219Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250274 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3655T>G has been reported in the literature in an individual affected with a personal and/or family history of breast cancer (Pereira_2022). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 35980532). ClinVar contains an entry for this variant (Variation ID: 438971). Based on the evidence outlined above, the variant was classified as uncertain significance.