Submissions for variant NM_000059.4(BRCA2):c.7978T>G (p.Tyr2660Asp)

dbSNP: rs80359029

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480484	SCV000567102	pathogenic	not provided	2015-07-09	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.7978T>G at the cDNA level, p.Tyr2660Asp (Y2660D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). Using alternate nomenclature, this variant has been previously published as BRCA2 8206T>G. BRCA2 Tyr2660Asp has been observed in multiple individuals with hereditary breast and ovarian cancer and has been reported to co-segregate with disease in affected family members (van der Hout 2006, Gomez-Garcia 2009, Mohammadi 2009). Cell based functional studies demonstrated impaired repair activity similar to other known pathogenic variants (Guidugli 2013). BRCA2 Tyr2660Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2660Asp occurs at a position that is conserved across species and is located within the DNA binding domain (Borg 2010). Multiple published computational models predict this variant to have a deleterious effect (Karchin 2008, Guidugli 2013, Moghadasi 2013) and in house In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000773273	SCV000906946	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-19	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with aspartic acid at codon 2660 of the BRCA2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts homology-directed DNA repair activity (PMID: 23108138, 24323938) and fails to complement the lethality phenotype in BRCA2-deficient mouse embryonic stem cells (PMID: 29988080). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 16683254, 19200354). In addition, several multifactorial likelihood models using health history and experimental data have suggested this variant have a high probability of being pathogenic (PMID: 19200354, 19563646, 29394989). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386986	SCV001587450	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 19563646). ClinVar contains an entry for this variant (Variation ID: 52458). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer and ovarian cancer (PMID: 16683254, 19200354, 19563646, 20406929). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2660 of the BRCA2 protein (p.Tyr2660Asp).
Ambry Genetics	RCV000773273	SCV002675773	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	The p.Y2660D variant (also known as c.7978T>G), located in coding exon 17 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7978. The tyrosine at codon 2660 is replaced by aspartic acid, an amino acid with highly dissimilar properties. In one study, this alteration was identified in nine breast and/or ovarian cancer families, and was reported to segregate with disease in eight individuals from five families (Gómez García EB et al. Breast Cancer Res., 2009 Feb;11:R8). Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be likely deleterious (Karchin R et al. Cancer Inform. 2008;6:203-16). This alteration was non-functional in homology-directed DNA repair (HDR) assays (Guidugli L et al. Cancer Res., 2013 Jan;73:265-75; Guidugli L et al. Am J Hum Genet, 2018 02;102:233-248; Hart SN et al. Genet Med, 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). This variant was found to be functionally deficient in a BRCA2-null mouse embryonic stem cell complementation assay (Mesman RLS et al. Genet Med, 2019 02;21:293-302). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077420	SCV000109218	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077420	SCV000147240	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1999-04-05	no assertion criteria provided	clinical testing