13-32340455-C-T

Position:

• chr13-32340455-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_000059.4(BRCA2):​c.6100C>T​(p.Arg2034Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,613,692 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2034H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (19 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:42 O:1
• Conservation: PhyloP100: -0.243

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 -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32340455-C-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 617766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006237477).
• BP6: Variant 13-32340455-C-T is Benign according to our data. Variant chr13-32340455-C-T is described in ClinVar as [Benign]. Clinvar id is 41558.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340455-C-T is described in Lovd as [Benign]. Variant chr13-32340455-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6100C>T	p.Arg2034Cys	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6100C>T	p.Arg2034Cys	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 515 AN: 152148 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00313 AC: 785 AN: 250958 Hom.: 2 AF XY: 0.00312 AC XY: 424 AN XY: 135692

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00497

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00463 AC: 6768 AN: 1461426 Hom.: 19 Cov.: 46 AF XY: 0.00446 AC XY: 3240 AN XY: 727016

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00409

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00558

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152266 Hom.: 3 Cov.: 33 AF XY: 0.00298 AC XY: 222 AN XY: 74460

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00534

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00480 Hom.: 7

Bravo AF: 0.00383

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00323 AC: 392

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00605

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:42 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:14

Likely benign, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 27, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	literature only	Counsyl	Feb 06, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000571 -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 10, 2011	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not specified Benign:11 Other:1

Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 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 p.Arg2034Cys variant has been identified in 42 out of 7668 proband chromosomes (frequency 0.005) in individuals with unilateral and contralateral breast cancer and familial breast and ovarian cancer phenotype, and also found in 39 out of 3186 control chromosomes (frequency 0.012) included in these studies (Johnson 2007, Schoumacher 2001, Wagner 1999, Capanu 2011, Borg 2010, Hondow 2011, Salazar 2006, Diez 2003, Simard 2006, Miramar 2008, Beristain 2007). It is also listed in dbSNP database coming from a “clinical source” (ID#: rs1799954) with a “global minor allele frequency of 0.001 (1000 genomes), therefore increasing the likelihood that this variant is benign. The p.Arg2034 is not conserved in mammals but was conserved in birds, reptiles, frogs and fish, therefore decreasing the likelihood that this variant has functional significance. Furthermore, the computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In the UMD database, this variant has been identified in 22 (out of 137) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 or BRCA2 mutation was also detected, further suggesting that this is a benign variant. In summary, based on the above information, this variant is 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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRCA2: BP4, BS2 -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 27, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -

Hereditary breast ovarian cancer syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2014	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 13, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 18, 2020	- -
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. -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 12, 2022

- -

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	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.16	T;T
Vest4		0.20
MVP		0.83
MPC		0.022
ClinPred		0.022	T
GERP RS		1.8
gMVP		0.22

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: rs1799954; hg19: chr13-32914592; COSMIC: COSV66461677;