Submissions for variant NM_000059.4(BRCA2):c.191C>T (p.Thr64Ile)

dbSNP: rs397507615

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215512	SCV000276687	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The p.T64I variant (also known as c.191C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 191. The threonine at codon 64 is replaced by isoleucine, an amino acid with similar properties. This alteration has been identified in multiple breast and/or ovarian cancer families (Hadjisavvas A et al. Cancer Genet. Cytogenet. 2004 Jun;151:152-6; Apessos A et al. Cancer Genet. 2018 Jan;220:1-12; Santonocito C et al. Cancers (Basel), 2020 May;12:). This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588169	SCV000694585	uncertain significance	not provided	2016-03-08	criteria provided, single submitter	clinical testing	Variant summary: The c.191C>T variant affects a conserved nucleotide, resulting in amino acid change from Thr to Ile. 5/5 in-silico tools predict damaging outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40. However, these predictions are not confirmed by experimental studies. This variant is not found in 121322 control chromosomes. In addition, one reputable database classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000215512	SCV000905894	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 64 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer in the literature (PMID: 15172753, 29310832). This variant has been identified in 1/251382 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	RCV001306617	SCV001495998	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 51228). 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 BRCA2 protein function. This missense change has been observed in individual(s) with a personal and/or family history of breast, ovarian, or pancreatic cancer (PMID: 15172753, 27882536, 29310832). This variant is present in population databases (rs397507615, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 64 of the BRCA2 protein (p.Thr64Ile).
GeneDx	RCV000588169	SCV002050535	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in families with breast and/or ovarian cancer (Hadjisavvas 2004, Loizidou 2017, Apessos 2018, Santonocito 2020); Also known as BRCA2 419C>T; This variant is associated with the following publications: (PMID: 15172753, 27882536, 29310832, 32438681, 32641407, 27535533)
Baylor Genetics	RCV003473309	SCV004211882	uncertain significance	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing