Submissions for variant NM_000059.4(BRCA2):c.4429A>G (p.Ile1477Val)

gnomAD frequency: 0.00002  dbSNP: rs1159807733

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586178	SCV000694770	uncertain significance	not specified	2021-03-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4429A>G (p.Ile1477Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4429A>G has been reported in the literature in at-least one individual affected with breast cancer (example, Fackenthal_2012). 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. 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 citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000637705	SCV000759176	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1477 of the BRCA2 protein (p.Ile1477Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 22034289). ClinVar contains an entry for this variant (Variation ID: 495464). 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 BRCA2 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.
Ambry Genetics	RCV001022464	SCV001184204	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-18	criteria provided, single submitter	clinical testing	The p.I1477V variant (also known as c.4429A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4429. The isoleucine at codon 1477 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer from Nigeria (Fackenthal JD et al. Int. J. Cancer, 2012 Sep;131:1114-23). 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.
Color Diagnostics, LLC DBA Color Health	RCV001022464	SCV002052491	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1477 of the BRCA2 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 an individual affected with breast cancer (PMID: 22034289). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001022464	SCV003850502	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	RCV004002393	SCV004845679	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1477 of the BRCA2 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 an individual affected with breast cancer (PMID: 22034289). 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.