Submissions for variant NM_000059.4(BRCA2):c.425G>T (p.Ser142Ile)

dbSNP: rs397507713

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213168	SCV000275905	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The c.425G>T variant (also known as p.S142I), located in coding exon 3 of the BRCA2 gene, results from a G to T substitution at nucleotide position 425. The serine at codon 142 is replaced by isoleucine, an amino acid with dissimilar properties. In addition, this change occurs in the last nucleotide of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep. 2022 Mar;12(1):4190). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Brandão R et al. Breast Cancer Res. Treat. 2011 Oct;129(3):971-82; Nix P et al. Fam Cancer, 2021 Jan). However, this alteration was able to rescue the growth defect in BRCA2-null mouse embryonic stem cells and these surviving cells maintained partial activity in a homology directed DNA repair functional assay (Mesman R et al. Genet Med 2020 Aug;22(8):1355-1365). This alteration is also identified in patients who collectively have a phenotype that is not consistent with a high risk BRCA2 pathogenic variant (Nix P et al. Fam Cancer, 2021 Jan). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000521547	SCV000617461	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast cancer (Brandao et al., 2011; Guindalini et al., 2022); Exonic splice variant resulting in the production of multiple transcripts, including potentially functional in-frame transcripts (Brandao et al., 2011; Mesman et al., 2020; Nix et al., 2021); Published functional studies demonstrate protein levels and homology-directed repair activity comparable to wildtype (Mesman et al., 2020); Not observed in large population cohorts (gnomAD); Also known as 653G>T; This variant is associated with the following publications: (PMID: 31911673, 23893897, 26913838, 30212499, 31131967, 31589614, 33469799, 35264596, 21638052, 32398771)
Mendelics	RCV000709287	SCV000838731	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000521547	SCV000887807	likely pathogenic	not provided	2018-08-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213168	SCV000911390	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 142 of the BRCA2 protein. This variant alters the conserved c.G at the last nucleotide position of exon 4 to c.T. RNA studies have shown this variant produces multiple transcripts causing out-of-frame skipping of exon 4 and transcripts causing in-frame skipping of exon 4 (PMID: 21638052, 32398771, 33469799). A functional study found that this variant complements the lethality of Brca2-deficient mouse embryonic stem cells and shows intermediate BRCA2 function in a homology-directed repair assay (PMID: 32398771). This variant has been reported in at least two individuals with a personal or family history of BRCA2-related cancer (PMID: 21638052, 33471991; Leiden Open Variation Database DB-ID BRCA2_001571, 35264596). 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	RCV002265580	SCV000916899	uncertain significance	not specified	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.425G>T (p.Ser142Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical splice 5' donor site. Several studies report a predicted impact of splicing leading to multiple transcripts including skipping of exon 4, exon 4-5 and exons 4-7 resulting in a population of potentially functional in-frame transcripts (example, Nix_2022). The variant was absent in 248562 control chromosomes. c.425G>T has been reported in the literature in an individual with a personal and family history of breast cancer (Brandao_2011) and in settings of multigene panel testing in an individual with breast cancer (example, Guindalini_2022). These data indicate that the variant may be associated with disease. At least one recent publication reports experimental evidence evaluating an impact on protein function (example, Mesman_2020). The most pronounced variant effect results in 66% of normal homology directed repair (HDR) activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely pathogenic, n=5; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging evidence outlined above, the variant was re-classified as uncertain significance.
Mendelics	RCV000988985	SCV001138957	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000709287	SCV001535997	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects codon 142 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with personal and family history of breast cancer (PMID: 21638052). ClinVar contains an entry for this variant (Variation ID: 51618). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant does not substantially affect BRCA2 function (PMID: 32398771). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 21638052, 27060066, 32398771; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
MGZ Medical Genetics Center	RCV000988985	SCV002579686	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-07-29	criteria provided, single submitter	clinical testing