rs276174831

Variant names:

• chr13-32337281-TC-AT
• rs276174831
• NM_000059.4:c.2926_2927delTCinsAT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):​c.2926_2927delTCinsAT​(p.Ser976Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000642 in 180 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S976F) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.00064 Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16 O:1
• Conservation: PhyloP100: 0.756
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 13-32337281-TC-AT is Benign according to our data. Variant chr13-32337281-TC-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 51372.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2926_2927delTCinsAT	p.Ser976Ile	missense_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.2926_2927delTCinsAT	p.Ser976Ile	missense_variant		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2557_2558delTCinsAT	p.Ser853Ile	missense_variant		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2926_2927delTCinsAT		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

GnomAD MNV AF: 0.000642 AC: 180 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

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. -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Sep 23, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP1_strong, PM2_supporting The c.2926_2927delinsAT variant (also known as p.S976I), located in coding exon 11 of the BRCA2 gene, results from an in-frame deletion of 2 nucleotides and insertion of AT at nucleotide positions 2926 to 2927 (BP1_strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. Also, the variant has not been reviewed neither in ClinVar nor in BRCA Exchange databases. Based on currently available information, the variant c.2926_2927delinsAT should be considered a likely benign variant. -

not specified Benign:3 Other:1

Jan 20, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jul 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Uncertain:1 Benign:2

Sep 08, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP1, BS1 -

May 02, 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.2926_2927delinsAT variant involves the alteration of two nucleotides resulting in an amino acid change from Ser to Ile. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.073%, predominantly observed in the African subpopulation at a frequency of 0.85%. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%) by 11-fold, suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in patients and controls in the literature and has been classified by multiple reputable clinical labs as "benign". Additionally, the variant was found to co-occur with pathogenic variants from several databases: BRCA1 c.3817C>T, p.Gln1273X (UMD); BRCA2 c.9026_9030delATCAT, p.Tyr3009_His3010?fs (BIC); BRCA1 c.815_824dupAGCCATGTGG, p.Thr276Alafs (BIC). Taken together, this variant has been classified as a benign. -

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

Dec 22, 2015

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Oct 12, 2021

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 cancer predisposition Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Ser976Ile variant was identified in 2 of 3116 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer (Lee_2008_18284688, Weitzel_2005_16030099). The variant was also identified in the following databases: dbSNP (ID: rs276174831) as “With other allele” , ClinVar (as benign by BIC, Invitae, Quest Diagnostics, Sinai Health System, LabCorp, CHEO, GeneDx, and Ambry Genetics, as likely benign by Counsyl and Color Genomics, and as uncertain significance by EGL Diagnostics), Clinvitae (with conflicting interpretations of pathogenicity), COGR (as benign by COGR consensus), LOVD 3.0 (13x), UMD-LSDB (11 x classified as neutral and co-occurring with a pathogenic BRCA1 variant p.Gln1273X), BIC Database (26 x in BIC with no classification). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, Zhejiang Colon Cancer Database. The variant was identified in the Exome Aggregation Consortium (August 8th 2016), and the Genome Aggregation Database (Feb 27, 2017) listed under two different dbSNP identification numbers: rs11571656; rs144862123; in both cases it was identified in 167 of approximately 23980 African population chromosomes (frequency: 0.0069) and was also observed in Latino in 9 of 34204 chromosomes, increasing the likelihood that this may be a low frequency allele without clinical significance. This variant is an in-frame deletion resulting in the removal of a serine (Ser) residue at codon 976; the impact of this alteration on BRCA2 protein function is not known. Although the p.Ser976 residue is not conserved in mammals, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Ser976Ile variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. One in silico study yielded inconclusive risk predictions for this variant (Lee_2008). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our labortory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76
Mutation Taster		=76/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs276174831; hg19: chr13-32911418; COSMIC: COSV104701430;