rs80358656

chr13-32338416-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000059.4(BRCA2):c.4061C>T(p.Thr1354Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,604,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. T1354S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:25 O:1
• Conservation: PhyloP100: 0.161

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.078579396).
• BP6: Variant 13-32338416-C-T is Benign according to our data. Variant chr13-32338416-C-T is described in ClinVar as [Benign]. Clinvar id is 51588.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338416-C-T is described in Lovd as [Benign]. Variant chr13-32338416-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4061C>T	p.Thr1354Met	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4061C>T	p.Thr1354Met	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151998 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000140 AC: 34 AN: 243546 Hom.: 0 AF XY: 0.000160 AC XY: 21 AN XY: 131438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.000515

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1452654 Hom.: 0 Cov.: 35 AF XY: 0.000125 AC XY: 90 AN XY: 721722

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000234

Gnomad4 ASJ exome AF: 0.000658

Gnomad4 EAS exome AF: 0.000304

Gnomad4 SAS exome AF: 0.0000481

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000100

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151998 Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6 AN XY: 74248

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:25 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:7

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
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	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 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 = 0.0000803 -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -

not specified Benign:6 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Dec 29, 2017	BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2019	Variant summary: BRCA2 c.4061C>T (p.Thr1354Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 243646 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00014 vs 0.00075), allowing no conclusion about variant significance. The variant, c.4061C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Arver_2001 , Capalbo_2006 , deSanjose_2003 , Laitman_2011) without strong evidence for causality. Cosegregation studies in a family with a history of breast cancer found that this variant did not segregate with disease (Jalkh_2017). Co-occurrences with other pathogenic variants have been reported [BRCA1 c.2071_2071delA, p.Arg691Aspfs (BIC database), CDH1 c.3G>A, p.Met1Ile (Jalkh_2017)], providing supporting evidence for a benign role. Ten other submitters including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as benign (n=3) or likely benign (n=7). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 17924331, 12845657, 21520273, 21156238, 21990134, 24055113, 25637381, 24323938, 24728327, 26306726, 11336395, 20104584, 16847550, 20960228, 26689913, 24504028, 27153395, 28202063) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Thr1354Met variant was identified in 6 of 5256 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast or ovarian cancer (Giannini 2006, Borg 2010, de Sanjosé 2003, Yang 2011). The variant was also identified in the following databases: dbSNP (ID: rs80358656) as ” With other allele”, ClinVar (17 x as benign by ENIGMA, VKGL data share, Invitae, Ambry Genetics, SCRP, as likely benign by EGL Genetics, COGR, Color Genomics, Integrated Genetics, Counsyl, GeneDx and as uncertain significance by BIC), COGR (as likely benign/benign), Cosmic (1x confirmed somatic ovarian carcinoma), LOVD 3.0 (7x as benign or predicted neutral), UMD-LSDB (17 x as likely neutral), BIC Database (12 x as uncertain significance), ARUP Laboratories (as “class 1,not pathogenic or of no clinical significance”). The variant was not identified in MutDB or Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 3 individuals with hereditary breast or ovarian cancer and 3 different co-occurring pathogenic variants were identified in each of these individuals (BRCA2, c.7007G>C, p.Arg2336Pro), (BRCA1, c.4096+1G>A, r.spl?) and (BRCA2, c.1103C>A, p.Ser368*), increasing the likelihood that the p.Thr1354Met variant does not have clinical significance. The variant was identified in control databases in 34 of 269620 chromosomes at a frequency of 0.00013 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23878 chromosomes (freq: 0.00004), Other in 2 of 6330 chromosomes (freq: 0.0003), Latino in 4 of 32684 chromosomes (freq: 0.0001), European Non-Finnish in 22 of 124492 chromosomes (freq: 0.00018), Ashkenazi Jewish in 4 of 9770 chromosomes (freq: 0.0004), and South Asian in 1 of 28178 chromosomes (freq: 0.000035); the variant was not observed in the East Asian or European Finnish populations. The p.Thr1354 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein (Capanu 2011, Easton 2007, Lindor 2012); this information is not very predictive of 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BRCA2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Likely 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 19, 2021	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 04, 2023	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 08, 2021

- -

Breast neoplasm Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	15
Dann	Benign	0.92
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.079	N
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.21
MVP		0.72
MPC		0.057
ClinPred		0.039	T
GERP RS		-3.0
gMVP		0.13

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: rs80358656; hg19: chr13-32912553; COSMIC: COSV66447605;