13-32338939-C-T

Position:

• chr13-32338939-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000059.4(BRCA2):​c.4584C>T​(p.Ser1528Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,660 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 Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:26
• Conservation: PhyloP100: 0.846

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 13-32338939-C-T is Benign according to our data. Variant chr13-32338939-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 51677.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338939-C-T is described in Lovd as [Benign]. Variant chr13-32338939-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.846 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4584C>T	p.Ser1528Ser	synonymous_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.4584C>T	p.Ser1528Ser	synonymous_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4215C>T	p.Ser1405Ser	synonymous_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4584C>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151982 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000224 AC: 56 AN: 250280 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135572

Gnomad AFR exome AF: 0.000690

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461560 Hom.: 0 Cov.: 45 AF XY: 0.000116 AC XY: 84 AN XY: 727062

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74346

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000408

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 12, 2000	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 21, 2017	- -
Benign, criteria provided, single submitter	literature only	Counsyl	May 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
Likely 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	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	BRCA2: BP4 -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 13, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 14, 2014	This alteration is classified as likely 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 21, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2015	Variant summary: The c.4584C>T variant, a synonymous mutation, lies in the middle of exon 11. This variant involves a non-conserved nucleotide and 5/5 in silico splice-site prediction tools via Alamut predict that the variant does not affect normal splicing. This prediction is consistent with the report from Caux-Moncoutier et al (Caux-Moncoutier et al 2009) in which the authors 'indirectly' show that the variant of interest does not result in allelic imbalance due to nonsense mediated decay of aberrant splice products. The variant was found in the general population at a frequency of 0.02% which does not exceed the maximal expected allele frequency of a pathogenic BRCA2 variant (which is 0.075%). However, the frequency of this variant in the Latino population is just above that of the maximal expected allele frequency (0.78%), which suggests this variant to be a polymorphism found mainly in populations of Latin descent. Indeed, several of the reported HBOC patients/families with the variant were from Spain, and co-occurrence and co-segregation were not reported for these patients, suggesting the true disease-causing mutation was not detected/presented. Furthermore, UMD reports co-occurrence with a possibly deleterious truncating BRCA2 variants c.6079dup (p.Arg2027LysfsX22) and c.4926_4935del (p.Asn1642LysfsX25) and with BRCA1 variant c.3331_3334delCAAG (p.Gln1111AsnfsX5) implicating that the variant of interest is in the benign spectrum. Additionally, publications (Osorio_BRCA2_Clin Genet_1998; Diez_BRCA2_HM_2003) and several clinical diagnostic laboratoris classify variant as Polymorphism/Bening/Likely Bening (without evidence to independently evaluate). Considering all evidence, the variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Nov 22, 2022

- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Ser1528Ser variant was identified in 25 of 1248 proband chromosomes (frequency: 0.04) from Spanish families with breast and ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals (Diez 2003).The variant was also identified in dbSNP (ID: rs80359788) “With Uncertain significance allele”, with a minor allele frequency of 0.001 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), LOVD, the ClinVar database (with one “uncertain significance” classification from BIC, benign submission from Invitae and benign submission from GeneDX), the BIC database (2X with unknown clinical importance), and UMD (21X as a neutral variant). In addition, Myriad classifies this as a polymorphism (personal communication). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3331_3334delCAAG (p.Gln1111AsnfsX5) of BRCA1gene and c.4926_4935del (p.Asn1642LysfsX25) of BRCA2 gene), increasing the likelihood that the p.Ser1528Ser variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 2 of 2000 chromosomes (frequency: 0.001), Exome Variant Server project in 3 of 4406 African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Ser1528Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.The p.Ser1528Ser variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs(SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as 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
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.0
DANN	Benign	0.55

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: rs80359788; hg19: chr13-32913076;