rs41293521

chr13-32394724-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):c.9292T>C(p.Tyr3098His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,898 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Y3098Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:20 O:1
• Conservation: PhyloP100: 0.618

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.032249957).
• BP6: Variant 13-32394724-T-C is Benign according to our data. Variant chr13-32394724-T-C is described in ClinVar as [Benign]. Clinvar id is 38227.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394724-T-C is described in Lovd as [Benign]. Variant chr13-32394724-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9292T>C	p.Tyr3098His	missense_variant	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9292T>C	p.Tyr3098His	missense_variant	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000291 AC: 73 AN: 250874 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135594

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000221 AC: 323 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 150 AN XY: 727056

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74514

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000222 Hom.: 1

Bravo AF: 0.000446

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:8

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 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 = 0.00000349 -
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	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Aug 24, 2015	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Aug 20, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 05, 2008	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 07, 2015	- -

not specified Uncertain:1 Benign:5 Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2018	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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Has been reported in 2 families with female breast and ovarian cancer (Serova-Sinilnikova 1997). Has been classified as benign by Akbari 2011 (based on Myriad classification criteria), Bodian 2011 (presence in controls), Guidugli 2014 (functional assay), Lindor 2012 (posterior probability model OR). No functional impact in DNA break repair assay (Guidugli 2013). B/LB by SCRP, GeneDx, Ambry, Counsyl, Invitae; VUS by BIC in ClinVar. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 11, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 29, 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

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 13, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 05, 2017

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2, p.Tyr3098His variant was identified in 6 of 5110 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and prostate cancer (Borg 2010, Edwards 2003, Gayther 1999, Serova-Sinilnikova 1997). The variant was also identified in dbSNP (ID: rs41293521) as “other”, Clinvitae database (classified as benign by ClinVar and Invitae; uncertain significance by ClinVar), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, Ambry Genetics, SCRP; likely benign by CHEO, GeneDx, Consyl; uncertain significance by BIC), GeneInsight COGR database (classified as benign, likely benign or uncertain significance by a clinical laboratories), the BIC database (33x with unknown clinical importance). This variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), the Exome Aggregation Consortium database (August 8th 2016) in 31 of 117284 chromosomes (freq. 0.0003) in the following populations: Latino in 15 of 11252 chromosomes (freq. 0.001), European in 15 of 93796 chromosomes (freq. 0.0002), African in 1 of 10290 chromosomes (freq. 0.0001), but was not seen in Asian, Finnish and other populations. In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3841C>T (p.Gln1281X), c.1953dup (p.Lys652GlufsX21); c.6405_6409delCTTAA (p.Asn2135LysfsX3)), increasing the likelihood that the p.Tyr3098His variant does not have clinical significance. The variant was also identified by our laboratory in two individuals with breast cancer. The p.Tyr3098 residue is not conserved in mammals and 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 addition, several functional studies classified this variant as class 1 (IARC) with probability of being deleterious 1.07×10−5 (Guidugli 2013, Lindor 2012). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	12
Dann	Benign	0.13
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.39	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.78	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.35
MVP		0.76
MPC		0.022
ClinPred		0.0033	T
GERP RS		1.6
gMVP		0.36

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: rs41293521; hg19: chr13-32968861;