rs1799955

Positions:

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

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000059.4(BRCA2):​c.7242A>G​(p.Ser2414=) 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:29
• Conservation: PhyloP100: 0.0960

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 Benign. Variant got -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 id is 126133.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32355095-A-G is described in Lovd as [Likely_benign]. Variant chr13-32355095-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7242A>G	p.Ser2414=	synonymous_variant	14/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7242A>G	p.Ser2414=	synonymous_variant	14/27	5	NM_000059.4	A2

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

GnomAD3 exomes AF: 0.225 AC: 56617 AN: 251236 Hom.: 6718 AF XY: 0.225 AC XY: 30611 AN XY: 135782

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 SAS exome AF: 0.220

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

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.433

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.223

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

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.225

Alfa AF: 0.204 Hom.: 2710

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:29

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 17, 2011	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 21.3 %. -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2016	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary breast ovarian cancer syndrome Benign:4

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 29, 2016	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -

Fanconi anemia complementation group D1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.7
DANN	Benign	0.75

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