rs397507698

Variant names:

• chr13-32338266-CTT-C
• rs397507698
• NM_000059.4:c.3914_3915delTT

Your query was ambiguous. Multiple possible variants found:

• chr13-32338266-CTT-C
• chr13-32338266-CTT-CT

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.3914_3915delTT​(p.Phe1305CysfsTer2) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.213

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 13-32338266-CTT-C is Pathogenic according to our data. Variant chr13-32338266-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3914_3915delTT	p.Phe1305CysfsTer2	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.3914_3915delTT	p.Phe1305CysfsTer2	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3545_3546delTT	p.Phe1182CysfsTer2	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3914_3915delTT		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/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides 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. To our knowledge, this variant has not been reported in individuals affected with BRCA2-related disorders in the literature. 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. -

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Clinical and Molecular Pathology, Medical Center Transhelix

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant c.3914_3915 causes the loss of two nucleotides in exon 11 of BRCA2 gene. This sequence alteration creates a frameshift (Phe1305CysfsTer2) and a consequent premature stop codon, leading to a non-functional polypeptide chain. Loss-of-function variants in BRCA genes are a known cancer-causing mechanism (PMID: 27452521) (PVS1). This variant is absent from population databases (PM2) (https://gnomad.broadinstitute.org/ version 4.1.0.). Our laboratory has detected BRCA2:c.3914_3915delTT variant in an individual affected with Hereditary Breast and Ovarian Cancer (PP4). This variant [IDs: 633101] has been identified as pathogenic three times (PP5). In conclusion, the ACMG/AMP criteria (MET criteria: PVS1, PM2, PP4, PP5) can be used to interpret the BRCA2:c.3914_3915 variant as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 19, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3914_3915delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 3914 to 3915, causing a translational frameshift with a predicted alternate stop codon (p.F1305Cfs*2). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Nov 15, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Dec 06, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.3914_3915delTT (p.Phe1305CysfsX2) 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 208654 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3914_3915delTT in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 06, 2023

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.Phe1305Cysfs*2) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 633101). For these reasons, this variant has been classified as Pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Nov 25, 2024

Clinical and Molecular Pathology, Medical Center Transhelix

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant c.3914_3915 causes the loss of two nucleotides in exon 11 of BRCA2 gene. This sequence alteration creates a frameshift (Phe1305CysfsTer2) and a consequent premature stop codon, leading to a non-functional polypeptide chain. Loss-of-function variants in BRCA genes are a known cancer-causing mechanism (PMID: 27452521) (PVS1). This variant is absent from population databases (PM2) (https://gnomad.broadinstitute.org/ version 4.1.0.). Our laboratory has detected BRCA2:c.3914_3915delTT variant in an individual affected with Hereditary Breast and Ovarian Cancer (PP4). This variant [IDs: 633101] has been identified as pathogenic three times (PP5). In conclusion, the ACMG/AMP criteria (MET criteria: PVS1, PM2, PP4, PP5) can be used to interpret the BRCA2:c.3914_3915 variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs397507698; hg19: chr13-32912403;