rs276174803

Variant names:

• chr13-32398608-C-GAATTATATCT
• rs276174803
• NM_000059.4:c.10095delCinsGAATTATATCT

Your query was ambiguous. Multiple possible variants found:

• chr13-32398607-TC-TGAATTATATCT
• chr13-32398607-TC-TNNNNNNNNNNN

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_Moderate PM2 BP6

The NM_000059.4(BRCA2):​c.10095delCinsGAATTATATCT​(p.Ser3366AsnfsTer4) variant causes a frameshift, stop gained, synonymous 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3365VNYI?) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift, stop_gained, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:17
• Conservation: PhyloP100: 0.00700

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0158 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32398608-C-GAATTATATCT is Benign according to our data. Variant chr13-32398608-C-GAATTATATCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125926.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.10095delCinsGAATTATATCT	p.Ser3366AsnfsTer4	frameshift_variant, stop_gained, synonymous_variant	Exon 27 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.10095delCinsGAATTATATCT	p.Ser3366AsnfsTer4	frameshift_variant, stop_gained, synonymous_variant	Exon 27 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9726delCinsGAATTATATCT	p.Ser3243AsnfsTer4	frameshift_variant, stop_gained, synonymous_variant	Exon 27 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2153delCinsGAATTATATCT		non_coding_transcript_exon_variant	Exon 26 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2153delCinsGAATTATATCT		3_prime_UTR_variant	Exon 26 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4 -

May 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Aug 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30113427, 22505045, 12569143) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Ser3366Asnfs*4 variant was identified in 19 of 9215 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic and hereditary breast and ovarian cancer and identified in 1 of 490 chromosomes (frequency: 0.002) from healthy individuals (Borg 2010, Hahn 2003, Koczowska 2016, Wojcik 2016, Ratajska 2008, Balabas 2010, Houdayer 2012, Meindl 2002, Kim 2005, Thomassen 2008, Machakova 2008, Stegel 2011). The variant was identified in ClinVar (classified as benign by Ambry Genetics, BIC, Integrated Genetics, and 2 other submitters, uncertain significance by PreventionGenetics, Western University and 2 other submitters and likely benign by Invitae, Pathway Genomics and 1 other submitter), LOVD 3.0 (observed 1x), UMD-LSDB (observed 25x) .The variant was not identified in dbSNP, Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In UMD-LSDB, the variant was observed in samples with co-occurring pathogenic BRCA1 variants (c.2959A>T p.Lys987*, c.1171G>T p.Glu391*). Additionally, the variant had no observed effect on both BRCA2 mRNA expression and in vitro splicing (Stordal 2013, Houdayer 2012). The c.10095delinsGAATTATATCT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3366 and leads to a premature stop codon at position 3369. This alteration is then predicted to result in a truncated or absent protein. Truncations downstream of the Lys3326 residue are predicted to retain the biological functions of BRCA2 and are not believed to be pathogenic, however this has not been tested experimentally (Borg 2010, Negura 2012). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

May 03, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c. 10095delinsGAATTATATCT (p.Ser3366Asnfs) variant in BRCA2 has been reported in the literature to be found in prostate, breast and ovarian cancer patients, without strong evidence for causality. The variant was identified in at least 1 healthy individual from the literature, but not amongst the 1000G, ExAC or and ESP cohort. Multiple reputable clinical labs/databases have classified the variant as benign/likely benign. The variant is located 51 amino acids from the end of the protein and 40 amino acids downstream from the c.9976A>T (p.Lys3326X) variant, which was proven to be non pathogenic and It is generally accepted that truncations downstream of Lys3326 are non-pathogenic. Additionally, the variant was found to co-occur with several pathogenic BRCA1/2 variants via UMD: BRCA2 c.17_18delAA (p.Lys6Argfs), BRCA1 c.2959A>T (p.Lys987X), BRCA1 c.1171G>T (p.Glu391X). The variant was also shown to have no effect on splicing (Houdayer_2012). The variant of interest shows strong evidence for neutrality, and has been classified as a benign variant. -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4

Jul 24, 2014

Pathway Genomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 17, 2010

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:2 Benign:1

Feb 02, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Interpretation was last updated within 1 year from 2/2/2016 11:04 AM -

Feb 12, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

missense or nonsense variant predicted to modify or truncate protein sequence at residues from position p.3309 onwards is considered highly unlikely to be clinically important as a high-risk variant; According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose this criterion: PM2 (supporting pathogenic): absent from controls -

Dec 22, 2015

Dr. Peter K. Rogan Lab, Western University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Sequenced patient with familial breast cancer -

not specified Benign:2

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 06, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 22, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma Pathogenic:1

Sep 11, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Dec 05, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Benign:1

Oct 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs276174803; hg19: chr13-32972745; COSMIC: COSV66338166; COSMIC: COSV66338166;