rs397507851

Variant names:

• chr13-32340760-CTTAAATG-C
• rs397507851
• NM_000059.4:c.6408_6414delAAATGTT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.6408_6414delAAATGTT​(p.Asn2137LysfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 0.793

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]

ACMG classification

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 13-32340760-CTTAAATG-C is Pathogenic according to our data. Variant chr13-32340760-CTTAAATG-C is described in ClinVar as [Pathogenic]. Clinvar id is 52086.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340760-CTTAAATG-C is described in Lovd as [Pathogenic]. Variant chr13-32340760-CTTAAATG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6408_6414delAAATGTT	p.Asn2137LysfsTer29	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6408_6414delAAATGTT	p.Asn2137LysfsTer29	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6039_6045delAAATGTT	p.Asn2014LysfsTer29	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6408_6414delAAATGTT		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM2_supporting; PM5_PTC_Strong -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 04, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 7 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 6636delAAATGTT, c.6406_6412del, and c.6631delTTAAATG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 20380699, 24549055, 25066507, 26360800, 28724667, 32772980, 34680878), and has been identified in 8 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -

Dec 22, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6408_6414delAAATGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 7 nucleotides at nucleotide positions 6408 to 6414, causing a translational frameshift with a predicted alternate stop codon (p.N2137Kfs*29). This mutations has been reported in an Estonian family affected with breast, ovarian, prostate and gastric cancers, a Danish family with multiple cases of prostate cancer and an individual with both male breast cancer and prostate cancer, and in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Tamboom K et al. Hered Cancer Clin Pract. 2010 Apr 9;8(1):4; Roed Nielsen H et al. Acta Oncol. 2016 Sep;55:38-44; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). Of note, this alteration is also designated as c.6631delTTAAATG and c.6406_6412del in published literature. 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn2137Lysfs*29) 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 prostate cancer and breast and ovarian cancer (PMID: 20380699, 24549055, 25066507, 26360800, 28724667). This variant is also known as 6636delAAATGTT and c.6406_6412del. ClinVar contains an entry for this variant (Variation ID: 52086). For these reasons, this variant has been classified as Pathogenic. -

Nov 27, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.6408_6414delAAATGTT (p.Asn2137LysfsX29) 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. The variant was absent in 240454 control chromosomes (gnomAD). c.6408_6414delAAATGTT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Tamboom_2010, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Malignant tumor of pancreas Pathogenic:1

Dec 06, 2017

3DMed Clinical Laboratory Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 29, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast, ovarian, and prostate cancer in the published literature (PMIDs: 20380699 (2010), 26360800 (2016), 28724667 (2017), and 29446198 (2018)). Therefore, the variant is classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Oct 18, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507851; hg19: chr13-32914897;