rs56957645

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000059.4(BRCA2):c.5744C>T(p.Thr1915Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,613,612 control chromosomes in the GnomAD database, including 679 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T1915T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 31 hom., cov: 33)

Exomes 𝑓: 0.027 ( 648 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:40O:1

Conservation

PhyloP100: -1.10

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026650429).

BP6

Variant 13-32340099-C-T is Benign according to our data. Variant chr13-32340099-C-T is described in ClinVar as [Benign]. Clinvar id is 41556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340099-C-T is described in Lovd as [Benign]. Variant chr13-32340099-C-T is described in Lovd as [Likely_benign]. Variant chr13-32340099-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2719/152214) while in subpopulation NFE AF= 0.0306 (2081/67978). AF 95% confidence interval is 0.0295. There are 31 homozygotes in gnomad4. There are 1269 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5744C>T	p.Thr1915Met	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.5744C>T	p.Thr1915Met	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2719

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0306

Gnomad OTH

AF:

0.0168

GnomAD3 exomes

AF:

0.0176

AC:

4420

AN:

250908

Hom.:

AF XY:

0.0180

AC XY:

2446

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.00892

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00886

Gnomad FIN exome

AF:

0.00866

Gnomad NFE exome

AF:

0.0290

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0274

AC:

40071

AN:

1461398

Hom.:

648

Cov.:

AF XY:

0.0271

AC XY:

19723

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00433

Gnomad4 AMR exome

AF:

0.00892

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00985

Gnomad4 FIN exome

AF:

0.0115

Gnomad4 NFE exome

AF:

0.0325

Gnomad4 OTH exome

AF:

0.0240

GnomAD4 genome

AF:

0.0179

AC:

2719

AN:

152214

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1269

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00578

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.00754

Gnomad4 NFE

AF:

0.0306

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0266

Hom.:

148

Bravo

AF:

0.0174

TwinsUK

AF:

0.0294

AC:

109

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0179

AC:

2167

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0258

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:40Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:11

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	- -
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 0.02375 (European), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 15, 2011	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 17, 2010	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:11Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 29, 2015	p.Thr1915Met in exon 11 of BRCA2: This variant is not expected to have clinical significance because it has been identified in 2.7% (1814/66580) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs4987117) and due to a lack of conservation across species, including >20 mammals which have a methionine (Met) at this position. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Thr1915Met variant was identified in 264 of 11658 proband chromosomes (frequency: 0.02) from individuals or families with breast and ovarian cancer (Borg 2010, D'Argenio 2015, Garre 2015, Schenkel 2016, Jalkh 2012, Serrano-Fernandez 2009, Meyer 2012, Cherbal 2012). The variant was also identified in the following databases: dbSNP (ID: rs4987117) as "With other allele", ClinVar (20X benign including review by expert panel ENIGMA, 3x likely benign, 2x uncertain significance), Clinvitae, GeneInsight-COGR (5x benign), Cosmic (3x, confirmed somatic, carcinoma of the large intestine and soft tissue), LOVD 3.0 (108x, predicted neutral), and the BIC Database (16x, not pathogenic). In UMD (41x, neutral biological significance) the variant was identified with co-occurring pathogenic variants: BRCA1 c.5137delG (p.Val1713X) and c.5266dup (p.Gln1756ProfsX74), BRCA2 c.3009_3010delCA (p.His1003GlnfsX5), c.5073dup (p.Trp1692MetfsX3), c.6405_6409delCTTAA (p.Asn2135LysfsX3), and c.7805G>C (p.Arg2602Thr), increasing the likelihood that the p.Thr1915Met variant does not have clinical significance. The variant was also identified by our laboratory in one individual with breast cancer. The variant was not identified in MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 4962 of 276776 chromosomes (61 homozygous) at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 125 of 24016 chromosomes (freq: 0.005), Other in 123 of 6456 chromosomes (freq: 0.02), Latino in 304 of 34410 chromosomes (freq: 0.01), European in 3746 of 126392 chromosomes (freq: 0.03), Ashkenazi Jewish in 161 of 10142 chromosomes (freq: 0.02), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 229 of 25748 chromosomes (freq: 0.009), and South Asian in 272 of 30752 chromosomes (freq: 0.009). The p.Thr1915 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -

not provided

Benign:6

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2016	- -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 17, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 10, 2015	- -
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, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -

Hereditary breast ovarian cancer syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Likely 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	Jan 15, 2014	- -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

- -

Fanconi anemia complementation group D1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.032

DANN

Benign

0.063

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0024

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

2.7

N;N

REVEL

Benign

0.14

Sift

Benign

0.33

T;T

Sift4G

Benign

0.38

T;T

Vest4

0.065

MPC

0.020

ClinPred

0.0068

GERP RS

0.62

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over