rs56087561

chr13-32339425-A-Cchr13-32339425-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000059.4(BRCA2):c.5070A>C(p.Lys1690Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,593,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:25
• Conservation: PhyloP100: 2.17

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20955938).
• BP6: Variant 13-32339425-A-C is Benign according to our data. Variant chr13-32339425-A-C is described in ClinVar as [Benign]. Clinvar id is 37942.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339425-A-C is described in Lovd as [Benign]. Variant chr13-32339425-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5070A>C	p.Lys1690Asn	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5070A>C	p.Lys1690Asn	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000221 AC: 52 AN: 235076 Hom.: 0 AF XY: 0.000251 AC XY: 32 AN XY: 127476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000770

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000189 AC: 272 AN: 1440994 Hom.: 0 Cov.: 46 AF XY: 0.000225 AC XY: 161 AN XY: 714624

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:25

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:6

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
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 = 0.0000000459 -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 07, 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	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
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	- -

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2023	The p.Lys1690Asn variant in BRCA2 is classified as likely benign because it has been identified in 0.29% (10/3466) of Ashkenazi Jewish chromosomes and 0.031% (21/68012) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1_Supporting -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2020	This variant is associated with the following publications: (PMID: 21952622, 21702907, 11304778, 25948282, 22366370, 28324225, 21990134, 17924331, 17997147, 15172753, 18951446, 24212087, 24323938, 22811390, 12161607, 24489791, 26689913, 19912264, 24504028, 27930734, 18256760, 32444794) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2016	Variant Summary: The c.5070A>C variant involves a conserved nucleotide in which 4/5 in silico tools predict a damaging outcome, and has a low prevalence in European controls (EVS: 2/8576 chrs and ExAC: 25/72,294 chrs). Though the observed allele frequency in general population is not higher than the maximal expected allele frequency for a BRCA2 pathogenic variant (1/1333) the presence of this variant in controls indicates that this variant might be a rare polymorphism. More importantly, the variant has been reported to co-occur with other deleterious variants in BRCA2 and BRCA1 (4 independent individuals who carry pathogenic variants in each BRCA1 and BRCA2, reported in UMD and BIC), strong evidence that this variantis benign. In addition, it has also been classified as benign by multiple reputable databases and clinical labs, databases and publications (Easton_2007, Lindor_2012 and Whiley_2014). There are no functional studies reported for the variant to date. Multifactorial probability based model also shows the variant to be benign. Taken together, this variant has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRCA2: BP1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 26, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 07, 2021	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Feb 02, 2024	The following ACMG criteria is used: BS1 (FAF > 0.01% in gnomAD), BP1_Strong (SpliceAI: less than or equal to 0.1) -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Chordoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

Integrative Tumor Epidemiology Branch, National Institutes of Health

Mar 22, 2021

No impact on ES cell survival or drug sensitivity (no impact on BRCA2 function) -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 01, 2022

- -

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

Dec 20, 2017

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

Not expected to have clinical significance. myriad calls a polymorphism (personal communication). 39X in BIC (unknown clinical importance), 12X in UMD and co-occurred with a second pathogenic variant 5X increasing the likelihood the p.Lys1690Asn variant does not have clinical significance. Lindor_2012, Posterior probability of being deleterious = 1.94x10-7 - iarc working group calls class 1 - not pathogenic. Not well conserved in mammals but in-silico software (AlignGVGD, Polyphen-2, SIFT, BLOSUM) do not agree. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.17	T;T
Vest4		0.38
MutPred		0.84		Loss of ubiquitination at K1690 (P = 0.0224);Loss of ubiquitination at K1690 (P = 0.0224);
MVP		0.93
MPC		0.14
ClinPred		0.19	T
GERP RS		3.2
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: rs56087561; hg19: chr13-32913562; COSMIC: COSV66465428;