Submissions for variant NM_000059.4(BRCA2):c.475+1G>T

dbSNP: rs81002797

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113645	SCV001161654	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998544
Invitae	RCV000044483	SCV000072496	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30883759; Invitae). 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: 31131967). ClinVar contains an entry for this variant (Variation ID: 51709). This variant is also known as IVS5+1G>T. Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 18703817, 24156927, 28724667, 29446198). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV000162896	SCV000213383	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	The c.475+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the BRCA2 gene. This alteration has been identified in multiple breast and/or ovarian cancer families to date (Palma MD et al. Cancer Res. 2008 Sep;68:7006-14; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973). This alteration as well as several close-match alterations at this same donor site results in skipping of coding exon 4 (Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420; Colombo M et al. PLoS One. 2013 Feb;8:e57173). Of note, this alteration is also designated as IVS5+1G>T in published literature. This alteration segregated with disease as reported in a multifactorial analysis model (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
GeneDx	RCV000255387	SCV000322287	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in out-of-frame exon skipping in a gene for which loss of function is a known mechanism of disease (Colombo et al., 2013; Fraile-Bethencourt et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 703+1G>T; This variant is associated with the following publications: (PMID: 24156927, 32772980, 25525159, 18703817, 28724667, 29446198, 23451180, 21523855, 30883759, 29673794, 31131967, 30702160, 31825140, 30787465, 34645131, 35957765)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113645	SCV000327080	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255387	SCV000600606	pathogenic	not provided	2017-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162896	SCV000683650	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 5 of the BRCA2 gene. RNA studies have detected the out-of-frame skipping of exon 5 in carrier-derived RNA and in a minigene splicing assay (PMID: 23451180, 30883759). This aberrant mRNA transcript is expected to result in an absent or non-functional protein product. This variant has been reported in three individuals affected with breast cancer (PMID: 28724667, 32963034) and in additional suspected hereditary breast and ovarian cancer families (PMID: 18703817, 24156927). A multifactorial analysis has reported a family history likelihood ratio for pathogenicity of 9.1893 from three pedigrees (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044483	SCV000694799	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-22	criteria provided, single submitter	clinical testing	Variant summary: The c.475+1G>T in a BRCA2 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical acceptor sequence, but functional studies are yet to be conducted to confirm those predictions. The variant has been reported in several affected individuals from HBOC families. The variant is absent from ExAC. Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390739	SCV004112526	pathogenic	BRCA2-related condition	2023-02-09	criteria provided, single submitter	clinical testing	The BRCA2 c.475+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as IVS5+1G>T , has been reported in multiple individuals with personal and/or family history of breast or ovarian cancer (Palma MD et al 2008. PubMed ID: 18703817; Tea MK et al 2013. PubMed ID: 24156927; Sun J et al 2017. PubMed ID: 28724667; Bang YJ et al 2021. PubMed ID: 34645131). In vitro functional studies show this variant results in exon skipping (Colombo M et al 2013. PubMed ID: 23451180; Fraile-Bethencourt E et al 2019. PubMed ID: 30883759). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003460586	SCV004216040	pathogenic	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044483	SCV004228153	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113645	SCV000146934	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing