Submissions for variant NM_000059.4(BRCA2):c.240A>G (p.Ile80Met)

gnomAD frequency: 0.00001  dbSNP: rs80358505

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043985	SCV000071998	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 80 of the BRCA2 protein (p.Ile80Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or head and neck squamous cell carcinoma (PMID: 10923033, 28678401). ClinVar contains an entry for this variant (Variation ID: 51277). 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	RCV000130843	SCV000185741	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.I80M variant (also known as c.240A>G), located in coding exon 2 of the BRCA2 gene, results from an A to G substitution at nucleotide position 240. The isoleucine at codon 80 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in a patient diagnosed with head and neck squamous cell carcinoma (Chandrasekharappa SC et al. Cancer, 2017 Oct;123:3943-3954). This variant was also reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species, however methionine is the reference amino acid in two 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	RCV000130843	SCV000688752	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 80 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 reported in an individual affected with head and neck carcinoma (PMID: 28678401). 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	RCV000781151	SCV000919021	uncertain significance	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.240A>G (p.Ile80Met) 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 251364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.240A>G, has been reported in the literature in individuals affected with breast cancer (UMD and BIC databases), and head and neck squamous cell carcinoma (Chandrasekharappa_2017). However, in at least two of these cases co-occurrences with other pathogenic variants have been reported (BRCA2 c.3599_3600delGT (p.Cys1200X) and BRCA1 c.3839_3843delinsAGGC (p.Ser1280X)), providing supporting evidence for a benign role. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 1/60466 cases, but was also found in 1/53461 controls (Dorling_2021, reported through LOVD). One functional study reported that this variant doesn't affect splicing in a minigene assay (Tubeuf_2020), however, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000781151	SCV001469414	uncertain significance	not specified	2021-03-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001283918	SCV001772075	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); Reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al., 2021); Also known as 468A>G; This variant is associated with the following publications: (PMID: 32641407, 31131967, 10923033, 33471991)
Baylor Genetics	RCV003460567	SCV004216064	uncertain significance	Familial cancer of breast	2024-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113305	SCV004846750	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 80 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 reported in an individual affected with head and neck carcinoma (PMID: 28678401). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113305	SCV000146426	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing