Variant rs80359398 details in Genebe, Genetics Data Aggregator

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32338043-TC-T is Pathogenic according to our data. Variant chr13-32338043-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 37853.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338043-TC-T is described in Lovd as [Pathogenic]. Variant chr13-32338043-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.3689del	p.Ser1230LeufsTer9	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.3689del	p.Ser1230LeufsTer9	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459612

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725844

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 05, 2024	The c.3689del (p.Ser1230Leufs9) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Ser1230Leufs9), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic. The c.3689del variant was reported in multiple individuals with ovarian, breast and colorectal cancer (PMID: 24728189, 29337092, 32034076, 27356891, 34994648). This variant is reported in ClinVar as pathogenic (ID: 37853). This variant is absent in the general population database (gnomAD). Therefore, the c.3689del (p.Ser1230Leufs*9) variant of BRCA2 has been classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 03, 2012	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 14, 2018	The BRCA2 c.3689delC: p.Ser1230fs variant (rs80359398), also known as 3917delC, is published in the medical literature in individuals with pancreatic or ovarian cancer (Lucas 2014, Song 2014). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 37853), but is not listed in the population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes one nucleotide, causes a frameshift, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Lucas AL et al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer. 2014 Jul 1;120(13):1960-7. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	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; Reported in association with hereditary breast and/or ovarian cancer (Melchor 2007, Song 2014, Copson 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 3917delC; This variant is associated with the following publications: (PMID: 24737347, 27356891, 24728189, 29337092, 18094411, 10923033, 27836010, 28152038, 30322717, 29446198) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast cancer, colorectal cancer, ovarian cancer, and pancreatic cancer in the published literature (PMID: 29446198 (2018), 27356891 (2016), 24737347 (2014), 24728189 (2014)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2020	Variant summary: BRCA2 c.3689delC (p.Ser1230LeufsX9) 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 was absent in 252552 control chromosomes. c.3689delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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 submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change creates a premature translational stop signal (p.Ser1230Leufs*9) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer, colorectal cancer, and a personal or family history of pancreatic ductal adenocarcinoma (PMID: 24728189, 24737347, 27356891). This variant is also known as 3917delC. ClinVar contains an entry for this variant (Variation ID: 37853). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 22, 2022	The c.3689delC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at position 3689, causing a translational frameshift with a predicted alternate stop codon (p.S1230Lfs*9). This mutation has been reported in individuals with hereditary ovarian and/or pancreatic cancer (Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Lucas AL et al. Cancer. 2014 Jul;120:1960-7). This mutation has also been reported in an individual who also carried a frameshift mutation in BRCA1 (Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	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 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. -

BRCA2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2024

The BRCA2 c.3689delC variant is predicted to result in a frameshift and premature protein termination (p.Ser1230Leufs*9). This variant has been reported in multiple individuals with various cancers including endometrial, colorectal, and ovarian cancers (Table S1, Song et al. 2014. PubMed ID: 24728189; Dobbins et al. 2016. PubMed ID: 27356891; Table S1, Carter et al. 2018. PubMed ID: 30322717). This variant has not been reported in a large population database, indicating it is rare. This variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37853/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

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SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs80359398

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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