Submissions for variant NM_000059.4(BRCA2):c.5542del (p.Ser1848fs)

dbSNP: rs80359519

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077353	SCV000300887	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044678	SCV000072691	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1848Valfs*15) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359519, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25371446). This variant is also known as 5770delA. ClinVar contains an entry for this variant (Variation ID: 51878). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130725	SCV000185613	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-16	criteria provided, single submitter	clinical testing	The c.5542delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 5542, causing a translational frameshift with a predicted alternate stop codon (p.S1848Vfs*15). This mutation has been reported in multiple individuals with breast and/or ovarian cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Torres-Mejía G et al, 2015 Mar;24:498-505; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3; Gallardo-Rincón D et al. Transl Oncol, 2020 Feb;13:212-220). This alteration has also been reported in six Hispanic families and classified as a pathogenic mutation in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000218498	SCV000279284	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; 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 5770delA; This variant is associated with the following publications: (PMID: 25371446, 26564481, 28152038, 29446198, 30630528, 28888541, 25186627, 30720243, 10923033, 30787465, 29922827, 34413315, 31853058, 31869745, 35406420, 31433991)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218498	SCV000296710	pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 34413315 (2021), 31869745 (2020), 30630528 (2019), 29446198 (2018), 28888541 (2017), 25186627 (2015), 25371446 (2014)). The frequency of this variant in the general population, 0.000004 (1/248448 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077353	SCV000327224	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077353	SCV000677684	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-03-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130725	SCV000683709	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 25371446) and has been identified in 6 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/248448 chromosomes 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	RCV000044678	SCV000694879	pathogenic	Hereditary breast ovarian cancer syndrome	2019-08-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5542delA (p.Ser1848ValfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248448 control chromosomes. c.5542delA has been reported in the literature in multiple individuals of Mexican/Hispanic/Latino/Carribean ancestry affected with Hereditary Breast and Ovarian Cancer (example Torres-Mejia_2015, Tung_2014, Rebbeck_2018, Fernandez-Lopez_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000218498	SCV001472430	pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	The BRCA2 c.5542delA; p.Ser1848fs variant (rs80359519) is reported in the literature in an individual with a personal and family history of breast cancer (Torres-Mejia 2015). This variant is also reported in ClinVar (Variation ID: 51878) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is found on a single chromosome in the Genome Aggregation Database (1/248448 alleles), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, other downstream truncating variants have been reported in individuals with breast and/or ovarian cancer and are considered disease-causing (Tedaldi 2017). Based on available information, the p.Ser1848fs variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classificationcriteria/ Tedaldi G et al. Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer. Oncotarget. 2017 Jul 18;8(29):47064-47075. PMID: 28423363. Torres-Mejia G et al. Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer. Cancer Epidemiol Biomarkers Prev. 2015 Mar;24(3):498-505. PMID: 25371446.
Baylor Genetics	RCV003460593	SCV004216021	pathogenic	Familial cancer of breast	2023-07-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077353	SCV000109150	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077353	SCV000146631	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing