13-32356526-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP6_Very_Strong

The NM_000059.4(BRCA2):c.7534C>T(p.Leu2512Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,614,224 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2512P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000040 (4 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:7 B:13
• Conservation: PhyloP100: 3.51

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_000059.4
• BP6: Variant 13-32356526-C-T is Benign according to our data. Variant chr13-32356526-C-T is described in ClinVar as [Benign]. Clinvar id is 52349.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32356526-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7534C>T	p.Leu2512Phe	missense_variant	15/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7534C>T	p.Leu2512Phe	missense_variant	15/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152228 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251352 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461878 Hom.: 4 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152346 Hom.: 0 Cov.: 31 AF XY: 0.0000671 AC XY: 5 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:7 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	This variant is associated with the following publications: (PMID: 24489791, 31131967, 19043619, 21120943, 27914478, 12228710, 25964535, 10923033, 18951461, 28283652, 30254663, 28288110, 30588330, 30199306, 32994724, 33067490) -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 05, 2023	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:3

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 0.000428 -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 17, 2006	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Nov 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Supporting)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not specified Uncertain:1 Benign:2

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2019	Variant summary: BRCA2 c.7534C>T (p.Leu2512Phe) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 348928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7534C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality (e.g. Zuntini_2018, Shimelis_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant(s) have been reported (BRCA1 c.4760C>G, p.Ser1587X), providing supporting evidence for a benign role (UMD database). In addition, several computational and multifactorial models suggest this variant as neutral or likely benign (Whiley_2014, Karchin_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters cite the variant as benign/likely benign (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 2018	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	Mar 01, 2022	- -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

not provided

North East Yorkshire Genomic Laboratory Hub

-

- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 30, 2022

- -

BRCA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Leu2512Phe variant was identified in 3 of 100,182 proband chromosomes (frequency: 0.00003) from individuals or families with breast or ovarian cancer (Caux-Moncoutier 2011, Maistro 2016, Shimelis 2017) and in 1 of 97,576 control chromosomes (frequency: 0.00001) from healthy individuals (Shimelis 2017). The variant was also identified in dbSNP (ID: rs80358980) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx and Counsyl; and as uncertain significance by Ambry Genetics and five other submitters), LOVD 3.0 (4x), UMD-LSDB (8x as unclassified variant), BIC Database (4x as unknown significance), and ARUP Laboratories (Likely not pathogenic or of little clinical significance) databases. The variant was identified in control databases in 6 of 246118 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5484 chromosomes (freq: 0.0002), Latino in 3 of 33576 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 111612 chromosomes (freq: 0.000009), and South Asian in 1 of 30770 chromosomes (freq: 0.00003), while it was not observed in the African, Ashkenazi Jewish, East Asian, or European Finnish populations. One clinical laboratory reports identifying this variant as homozygous variant in an individual with no personal or family history of Fanconi anemia. The p.Leu2512 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.036	D;D
Vest4		0.45
MVP		0.95
MPC		0.17
ClinPred		0.56	D
GERP RS		5.5
gMVP		0.39

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: rs80358980; hg19: chr13-32930663; COSMIC: COSV105932277;