rs56248502

chr13-32338445-A-Cchr13-32338445-A-Gchr13-32338445-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.4090A>C(p.Ile1364Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000899 in 1,611,934 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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. I1364M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (8 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:31 O:1
• Conservation: PhyloP100: 0.184

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=0.00439927).
• BP6: Variant 13-32338445-A-C is Benign according to our data. Variant chr13-32338445-A-C is described in ClinVar as [Benign]. Clinvar id is 51592.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338445-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00511 (779/152304) while in subpopulation AFR AF= 0.0179 (746/41576). AF 95% confidence interval is 0.0169. There are 7 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4090A>C	p.Ile1364Leu	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4090A>C	p.Ile1364Leu	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 776 AN: 152186 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00124 AC: 310 AN: 249354 Hom.: 4 AF XY: 0.000973 AC XY: 131 AN XY: 134680

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000459 AC: 670 AN: 1459630 Hom.: 8 Cov.: 35 AF XY: 0.000400 AC XY: 290 AN XY: 725868

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.000789

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000820

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000978

GnomAD4 genome AF: 0.00511 AC: 779 AN: 152304 Hom.: 7 Cov.: 33 AF XY: 0.00479 AC XY: 357 AN XY: 74480

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000707 Hom.: 3

Bravo AF: 0.00562

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:31 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:11

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
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	literature only	Counsyl	May 14, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02236 (African), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Ile1364Leu variant has been previously observed in our laboratory, and has been reported in the literature in 11/2200 proband chromosomes of individuals with breast cancer. However, no controls were tested to establish the frequency of the variant in the general population (Borg_2010_, Caux-Moncoutier_2009_, Haffty_2006_, Haffty_2009_, Tazzite_2012_). It is listed in the dbSNP database as coming from a "clinical source" (ID#:rs56248502) with a global minor allele frequency (MAF) of 0.005 (1000 Genomes). The variant has been reported in the UMD (x17), BIC (x53) and CNPHI databases. In the UMD database, the variant was observed to co-occur with other BRCA2 pathogenic mutations: c.6159delT (p.Ala2054LeufsX16) and c.8548_8551delGAAG (p.Glu2850GlnfsX12), increasing the likelihood that the p.Ile1364Leu variant does not have any clinical significance. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the p.Ile1364Leu variant is classified as benign. -

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 29, 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	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 03, 2018	- -

Hereditary breast ovarian cancer syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
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	Apr 15, 2014	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2022	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 08, 2016

- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 01, 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. -

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	0.094
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.27
Dann	Benign	0.86
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.044	N
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.11
Sift	Benign	0.17	T;T
Sift4G	Benign	0.71	T;T
Vest4		0.38
MutPred		0.26		Gain of catalytic residue at I1364 (P = 0.0153);Gain of catalytic residue at I1364 (P = 0.0153);
MVP		0.69
MPC		0.021
ClinPred		0.0055	T
GERP RS		-2.4
gMVP		0.095

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: rs56248502; hg19: chr13-32912582; COSMIC: COSV104430664;