chr13-32340099-C-T

Position:

• chr13-32340099-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign reviewed by expert panel U:2 B:40 O:1
• Conservation: PhyloP100: -1.10

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 -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	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	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.: 31 Cov.: 33

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.: 55 AF XY: 0.0180 AC XY: 2446 AN XY: 135670

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.: 49 AF XY: 0.0271 AC XY: 19723 AN XY: 726980

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.: 31 Cov.: 33 AF XY: 0.0170 AC XY: 1269 AN XY: 74432

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: 25

ESP6500EA AF: 0.0291 AC: 250

ExAC AF: 0.0179 AC: 2167

Asia WGS AF: 0.00577 AC: 21 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0258

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign: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:11 Other: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	T
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	N
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs4987117; hg19: chr13-32914236; COSMIC: COSV66459591;