rs28897717

chr13-32337299-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):c.2944A>C(p.Ile982Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,612,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I982M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: 3.88

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12680367).
• BP6: Variant 13-32337299-A-C is Benign according to our data. Variant chr13-32337299-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51375.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=6, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.2944A>C	p.Ile982Leu	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.2944A>C	p.Ile982Leu	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000402 AC: 10 AN: 248978 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000418 AC: 61 AN: 1460338 Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 31 AN XY: 726416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000248 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 27, 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	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 27, 2021	- -

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 20, 2022	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2024	BS1_sup, BS4, BP1_strong, BP5_mod -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2017	Variant summary: The BRCA2 c.2944A>C (p.Ile982Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 5/120330 control chromosomes at a frequency of 0.0000416, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature in an affected individual, without strong evidence for causality. Three clinical diagnostic laboratories classified this variant as uncertain significance, and one other lab classified it as benign, all without evidence for independent evaluaiton. UMD and BIC databases cite this variant in three individuals as co-occurring with pathogenic variants BRCA1 c.4327C>T (p.Arg1443X), BRCA1 c.4964_4982del (p.Ser956=fs), and BRCA2 c.7638-7647del (p.Lys257X), respectively, supporting the non-pathogenic role of this variant. Taken together, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -

not specified Uncertain:1 Benign:1

Uncertain significance, 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	GeneDx	Feb 15, 2018	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. -

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Supporting)+BP1(Strong)+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) -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

BRCA2, EXON11, c.2944A>C, p.Ile982Leu, Heterozygous, Likely Benign The BRCA2 p.Ile982Leu variant was identified in 1 of 512 proband chromosomes (frequency: 0.002) from French Canadian individuals or families with hereditary breast and/or ovarian cancer (Simard 2007). The variant was also identified in dbSNP (ID: rs28897717) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, Quest Diagnostics, Invitae, BIC and our laboratory; and as benign by Ambry Genetics), LOVD 3.0 (3 entries, effect unknown or not classified), UMD-LSDB (9 entries for this variant including one patient with a co-occurring, pathogenic BRCA2 mutation (c.7638_7647del, p.Lys254X) and another with a co-occurring, pathogenic BRCA1 mutation (c.4327C>T, p.Arg1443X), and the BIC Database (11 entries, classification pending). The variant was also identified by our laboratory in 2 individuals with breast cancer, however this variant does not appear to segregate with disease as the affected mother of one of these patients is negative for this variant, decreasing the likelihood that this variant may have clinical significance. The variant was identified in control databases in 8 of 244434 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5442 chromosomes (freq: 0.0002), European Non-Finnish in 7 of 110922 chromosomes (freq: 0.00006), but not in the African, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ile982Leu residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.93
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.56	N;N
REVEL	Benign	0.11
Sift	Benign	0.15	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.27
MutPred		0.17		Loss of methylation at K985 (P = 0.0682);Loss of methylation at K985 (P = 0.0682);
MVP		0.76
MPC		0.023
ClinPred		0.064	T
GERP RS		5.8
gMVP		0.14

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: rs28897717; hg19: chr13-32911436;