rs55953736

Positions:

• chr13-32340702-A-G
• chr13-32340702-A-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.6347A>G​(p.His2116Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,609,496 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. H2116D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:34 O:1
• Conservation: PhyloP100: 1.50

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=0.004720032).
• BP6: Variant 13-32340702-A-G is Benign according to our data. Variant chr13-32340702-A-G is described in ClinVar as [Benign]. Clinvar id is 41561.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340702-A-G is described in Lovd as [Benign]. Variant chr13-32340702-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00377 (574/152326) while in subpopulation AFR AF= 0.0123 (513/41582). AF 95% confidence interval is 0.0115. There are 5 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6347A>G	p.His2116Arg	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6347A>G	p.His2116Arg	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 573 AN: 152208 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00108 AC: 265 AN: 245524 Hom.: 2 AF XY: 0.000835 AC XY: 111 AN XY: 132962

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.000841

GnomAD4 exome AF: 0.000421 AC: 613 AN: 1457170 Hom.: 4 Cov.: 47 AF XY: 0.000359 AC XY: 260 AN XY: 724722

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152326 Hom.: 5 Cov.: 33 AF XY: 0.00379 AC XY: 282 AN XY: 74486

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.00453

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000867 AC: 4 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:34 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:9

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 20, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 18, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 28, 2016	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.025 (African), derived from 1000 genomes (2013-05-02). -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 15, 2015	- -

not specified Benign:7 Other:1

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	Genetic Services Laboratory, University of Chicago	Oct 25, 2017	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.His2116Arg variant has been reported in the literature in 13/19710 proband chromosomes of individuals with breast cancer and prostate cancer; it was not detected in the 122 control chromosomes tested (Berg_2012_22995991, Borg_2010_20104584, Carvalho_2007_17308087, Caux-Moncoutier_2011_21120943, Haffty_2006_15983021, Johnston_2012_22703879, Kote-Jarai_2011_21952622, Lee_2008_18284688, Tazzite_2012_22425665), however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. It has also been reported in the HGMD, BIC(x88 as not clinically important), Exome Variant Server and BOCs databases. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs55953736) with a global minor allele frequency (MAF) of 0.002 (1000 Genomes) and was also identified by the EVS project as a low frequency variant. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. It was identified 18x in the UMD database, 6x as co-occuring with a second pathogenic variant, increasing the likelihood this variant does not have clinical significance. Furthermore, Myriad genetics classifies this variant as a polymorphism (personal communication). In summary, this variant meets our criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -

Hereditary cancer-predisposing syndrome Benign:6

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 29, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 24, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 16, 2018	- -
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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 04, 2016	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRCA2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary breast ovarian cancer syndrome Benign:4

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	Mar 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -

Breast and/or ovarian cancer Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 14, 2022	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 20, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.87
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.26	N
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.32	T;T
Vest4		0.41
MVP		0.87
MPC		0.082
ClinPred		0.024	T
GERP RS		4.3
gMVP		0.25

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: rs55953736; hg19: chr13-32914839; COSMIC: COSV66457909;