13-32338613-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):c.4258G>T(p.Asp1420Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,596,994 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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. D1420V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (46 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:39 O:2
• Conservation: PhyloP100: 0.305

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32338615-T-AA is described in ClinVar as [Pathogenic]. Clinvar id is 1200705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073898137).
• BP6: Variant 13-32338613-G-T is Benign according to our data. Variant chr13-32338613-G-T is described in ClinVar as [Benign]. Clinvar id is 41549.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338613-G-T is described in Lovd as [Benign]. Variant chr13-32338613-G-T is described in Lovd as [Pathogenic]. Variant chr13-32338613-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00599 (912/152226) while in subpopulation NFE AF= 0.00777 (528/67976). AF 95% confidence interval is 0.00722. There are 9 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4258G>T	p.Asp1420Tyr	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4258G>T	p.Asp1420Tyr	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152108 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00650 AC: 1589 AN: 244580 Hom.: 14 AF XY: 0.00682 AC XY: 905 AN XY: 132706

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00846

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00648 AC: 9355 AN: 1444768 Hom.: 46 Cov.: 35 AF XY: 0.00667 AC XY: 4771 AN XY: 715584

Gnomad4 AFR exome AF: 0.00110

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00124

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00823

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.00660

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.00599 AC: 912 AN: 152226 Hom.: 9 Cov.: 33 AF XY: 0.00679 AC XY: 505 AN XY: 74422

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.00777

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00661 Hom.: 6

Bravo AF: 0.00417

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00538 AC: 46

ExAC AF: 0.00671 AC: 814

Asia WGS AF: 0.00491 AC: 17 AN: 3474

EpiCase AF: 0.00641

EpiControl AF: 0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:39 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:13 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Jan 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 = 0.000102 -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	-	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 04, 2017	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2013	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, 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	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 12, 2016	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BRCA2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 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. -

Hereditary breast ovarian cancer syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2014	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 06, 2016

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Asp1420Tyr variant has been previously reported in the literature in 203 of 18968 proband chromosomes (frequency of 0.011) with breast and ovarian cancer, and was also identified in 109 of 8530 (frequency of 0.013) control chromosomes increasing the likelihood that this is a low frequency benign variant It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897727) with a global minor allele frequency (MAF) of 0.001/2, and has an average heterozygosity of 0.008+/-0.062, increasing the likelihood that it is a benign variant. The Asp1420 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Functional studies have shown that compared to the wild-type protein, the p.Asp1420Tyr variant showed similar repair capacity and protein interactions, particularly with RAD51 (Davies_2001_11239456, Galkin_2005_15937124, Kuznetsov_2008_18607349). In addition, in two studies, one of which was a case control study, the allele frequency was higher in controls compared to the proband (Dombernowsky_2009_19661094, Stuppia_2003_12872265), thereby increasing the likelihood that this variant does not have clinical significance. Myriad genetics classifies this variant as a polymorphism, increasing the likelihood this variant is benign. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in these individuals, but based on the above information this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Uncertain	0.99
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.50	N
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Benign	0.15
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.0070	D;D
Vest4		0.35
MVP		0.81
MPC		0.024
ClinPred		0.012	T
GERP RS		1.1
gMVP		0.27

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: rs28897727; hg19: chr13-32912750; COSMIC: COSV66451253;