13-32341176-G-T

Position:

• chr13-32341176-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000059.4(BRCA2):​c.6821G>T​(p.Gly2274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,613,926 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (5 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:25
• Conservation: PhyloP100: 1.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006433964).
• BP6: Variant 13-32341176-G-T is Benign according to our data. Variant chr13-32341176-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=2, Benign=5}. Variant chr13-32341176-G-T is described in Lovd as [Likely_benign]. Variant chr13-32341176-G-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6821G>T	p.Gly2274Val	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.6821G>T	p.Gly2274Val	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6452G>T	p.Gly2151Val	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6821G>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00149 AC: 373 AN: 250294 Hom.: 2 AF XY: 0.00151 AC XY: 205 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.000759

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000779 AC: 1139 AN: 1461616 Hom.: 5 Cov.: 35 AF XY: 0.000745 AC XY: 542 AN XY: 727116

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:25

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 12, 2015	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
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	MGZ Medical Genetics Center	Nov 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Strong)+BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	This variant is associated with the following publications: (PMID: 20104584, 20380699, 9971877, 20127978, 16489001, 21990134, 21203900, 21702907, 27495310, 12601471, 28324225, 27882345, 20167696, 24094589, 25348012, 23555315, 27527004, 26580448, 30611917) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	BRCA2: BP1, BP4 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -

Hereditary cancer-predisposing syndrome Benign:6

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 16, 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	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 08, 2024	- -

Breast and/or ovarian cancer Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 02, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Feb 24, 2014	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Fanconi anemia complementation group D1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Oct 23, 2022

The BRCA2 c.6821G>T variant was found by WES in heterozygous state in female patient (47 y.o., Caucasian) with bilateral breast cancer. No additional rare candidate variants (Class III-V of pathogenicity) were found. The variant is located in a conserved domain that interacts with HSF2BP (PMID:31242413) and located close to a region that forms lattice contacts [aa 2276–2282](PMID:34373645). The variant is in Genome Aggregation Database (gnomAD) with total MAF 0.001590 (Date of access 17-10-2022) and the frequency is within prevalence of deleterious mutations in BRCA1 and BRCA2 (Mutation Prevalence Tables by Myriad Genetics Laboratories). ClinVar contains entry on this variant (Variation ID: 52199) with multiple submissions evaluating variant as “Likely benign”. Various articles describe variant with conflicting interpretation ranging from “Benign” to “Probably Pathogenic” (PMID: 30611917, 28324225, 27882345, 27527004, 27495310, 26580448, 25348012, 24094589, 23555315, 21702907, 21203900, 20380699, 20167696, 20127978, 20104584, 16489001, 9971877). In silico predictions show “Benign” or “Uncertain” based on calibrated prediction (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: BP4. -

BRCA2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Gly2274Val variant was identified in 8 of 7752 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was present in 1 of 2986 control chromosomes (frequency: 0.0003) from healthy individuals (Wagner 1999, Chenevix-Trench 2006, Borg 2010, Morgan 2010, Tamboom 2010, Capanu 2011, Jarhelle 2016, Konecny 2011). The variant was identified in dbSNP (rs55712212) as 'Auwith other allele'Au, ClinVar (classified as likely benign by GeneDx, Counsyl, PreventionGenetics and 4 other submitters; as benign by Color, Invitae, Ambry Genetics and SCRP; and as uncertain significance by BIC, Illumina and 2 other submitters ), LOVD 3.0 (observed 25x) and UMD-LSDB (observed 5x). The variant was identified in control databases in 445 of 267,156 chromosomes (2 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 331 of 25,104 chromosomes (freq: 0.01), Other in 9 of 6654 chromosomes (freq: 0.001), European in 104 of 117,702 chromosomes (freq: 0.0008), and Latino in 1 of 35,100 chromosomes (freq: 0.00003); it was not observed in the African, Ashkenazi Jewish, East Asian or South Asian populations. In multiple studies using multifactorial probability models, likelihood ratios predicted the variant to be 'Auneutral'Au (Chenevix-Trench 2006, Lindor 2012). The p.Gly2274 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; 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) 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.0064	T;T
MetaSVM	Uncertain	-0.19	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.20	T;T
Sift4G	Benign	0.54	T;T
Vest4		0.43
MVP		0.89
MPC		0.16
ClinPred		0.090	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.091

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs55712212; hg19: chr13-32915313;