rs1799955

Variant names:

• chr13-32355095-A-G
• rs1799955
• NM_000059.4:c.7242A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32355095-A-G
• chr13-32355095-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000059.4(BRCA2):​c.7242A>G​(p.Ser2414Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,446 control chromosomes in the GnomAD database, including 41,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S2414S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3839 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37436 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:31
• Conservation: PhyloP100: 0.0960
• Publications: 105 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 13-32355095-A-G is Benign according to our data. Variant chr13-32355095-A-G is described in ClinVar as Benign. ClinVar VariationId is 126133.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.096 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7242A>G	p.Ser2414Ser	synonymous_variant	Exon 14 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7242A>G	p.Ser2414Ser	synonymous_variant	Exon 14 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6873A>G	p.Ser2291Ser	synonymous_variant	Exon 14 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7242A>G		non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33669 AN: 152022 Hom.: 3840 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.225 AC: 56617 AN: 251236 AF XY: 0.225

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.222 AC: 323719 AN: 1461306 Hom.: 37436 Cov.: 36 AF XY: 0.222 AC XY: 161245 AN XY: 726984

African (AFR) AF: 0.214 AC: 7149 AN: 33456

American (AMR) AF: 0.180 AC: 8069 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5544 AN: 26124

East Asian (EAS) AF: 0.433 AC: 17163 AN: 39660

South Asian (SAS) AF: 0.220 AC: 18995 AN: 86246

European-Finnish (FIN) AF: 0.232 AC: 12406 AN: 53404

Middle Eastern (MID) AF: 0.202 AC: 1164 AN: 5764

European-Non Finnish (NFE) AF: 0.216 AC: 239753 AN: 1111570

Other (OTH) AF: 0.223 AC: 13476 AN: 60368

GnomAD4 genome AF: 0.221 AC: 33672 AN: 152140 Hom.: 3839 Cov.: 32 AF XY: 0.225 AC XY: 16723 AN XY: 74376

African (AFR) AF: 0.216 AC: 8954 AN: 41490

American (AMR) AF: 0.183 AC: 2796 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 738 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2043 AN: 5166

South Asian (SAS) AF: 0.220 AC: 1058 AN: 4820

European-Finnish (FIN) AF: 0.238 AC: 2519 AN: 10592

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14899 AN: 67992

Other (OTH) AF: 0.225 AC: 476 AN: 2116

Alfa AF: 0.207 Hom.: 3719

Bravo AF: 0.219

Asia WGS AF: 0.257 AC: 895 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.213

ClinVar

Significance: Benign

Submissions summary: Benign:31

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:11

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2014

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

High frequency in a 1kG or ESP population: 21.3 %. 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. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 12, 2015

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3864 (Asian), 0.1585 (African), 0.219 (European), derived from 1000 genomes (2012-04-30). -

Mar 17, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:8

May 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser2414Ser in exon 14 of BRCA2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 38.47% (3323/8638) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs1799955). -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 07, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Ser2414Ser variant was identified globally in 609 of 3040 proband chromosomes (frequency: 0.200) from individuals or families with familial and sporadic breast cancer, and was present in 68 of 364 control chromosomes (frequency: 0.187) from healthy individuals (Akilzhanova 2013, Fackenthal 2012, Jalkh 2012, Toh 2008, Marchina 2010, Saxena 2006, Diez 2003). The variant was identified in dbSNP (ID: rs1799955) “With benign allele”, in the 1000 Genomes Project in 271 of 1165 chromosomes (frequency: 0.2326), HAPMAP-CEU in 22 of 116 chromosomes (frequency: 0.19), HAPMAP-YRI in 25 of 118 chromosomes (frequency: 0.212), HAPMAP-HCB in 29 of 90 chromosomes (frequency: 0.322), NHLBI Exome Sequencing Project (Exome Variant Server) in 1834 of 8600 European American alleles (frequency: 0.2132) and in 915 of 4600 African American alleles (frequency: 0.2077), and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 27219 (heterozygous) and 3228 (homozygous) of 121288 chromosomes (frequency: 0.2244) (or 3988 East Asian individuals, 1740 European(Finnish), 229 Other, 2430 African, 2263 Latino, 3954 South Asian, and 15843 European(Non-Finnish) individuals). The variant was also identified in the Clinvitae database (5X), LOVD, the ClinVar database (classified as a benign variant by multiple submitters with no conflicts; by the Sharing Clinical Reports Project, derived from Myriad reports, BIC, Emory Genetics, Ambry Genetics, GeneDx, and Counsyl), GeneInsight COGR database (1X, classified as “uncertain” by a clinical laboratory), the BIC database (183X with no clinical importance), and in UMD (7X classified as neutral and co-occuring with a pathogenic variant p.Lys82X). The p.Ser2414Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:4

Dec 20, 2013

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cancer of breast Benign:2

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: 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. -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.7
DANN	Benign	0.75
PhyloP100		0.096
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799955; hg19: chr13-32929232; COSMIC: COSV66447569;