Submissions for variant NM_000059.4(BRCA2):c.4178C>T (p.Ala1393Val)

gnomAD frequency: 0.00002  dbSNP: rs398122776

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703970	SCV000108613	likely benign	not provided	2020-10-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25583476, 28301460, 30287823)
Ambry Genetics	RCV000165267	SCV000215983	likely benign	Hereditary cancer-predisposing syndrome	2019-04-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000410711	SCV000488362	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-08	criteria provided, single submitter	clinical testing
Invitae	RCV000472348	SCV000549793	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1393 of the BRCA2 protein (p.Ala1393Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 89047). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074528	SCV000694748	uncertain significance	not specified	2021-11-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4178C>T (p.Ala1393Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 266090 control chromosomes (gnomAD and publication), however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4178C>T has been reported in the literature in individuals affected with cancer, including breast cancer and colorectal cancer (e.g. Kim_2019, Fujita_2020, Guo_2020), but it was also reported in unaffected controls (Momozawa_2018, Dorling_2021). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as benign/likely benign, and two classfied it as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165267	SCV000903138	benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165267	SCV002533854	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165267	SCV003848746	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).
CeGaT Center for Human Genetics Tuebingen	RCV001703970	SCV004132983	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PM2, BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358513	SCV001554268	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ala1393Val variant was identified in 1 of 684 proband chromosomes (frequency: 0.001) from individuals with gastric cancer and was present in 2 of 24,980 control chromosomes (frequency: 0.0008) from healthy individuals (Chen 2015, Momozawa 2018). The variant was identified in dbSNP (rs398122776) as “with uncertain significance allele”, in ClinVar (interpreted as "uncertain significance" by Invitae and 2 others, "likely benign" by Ambry Genetics and 1 other and "benign" by Color), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 5x). The variant was identified in control databases in 1 of 236,638 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15,100 chromosomes (freq: 0.00007), but not in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala1393 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.