13-32370532-T-C

Position:

• chr13-32370532-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000059.4(BRCA2):​c.8462T>C​(p.Ile2821Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 7.95

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32370532-T-C is Benign according to our data. Variant chr13-32370532-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52595.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8462T>C	p.Ile2821Thr	missense_variant	19/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8462T>C	p.Ile2821Thr	missense_variant	19/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8093T>C	p.Ile2698Thr	missense_variant	19/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*520T>C		non_coding_transcript_exon_variant	18/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*520T>C		3_prime_UTR_variant	18/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 04, 2023

Variant summary: BRCA2 c.8462T>C (p.Ile2821Thr) results in a non-conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8462T>C in individuals affected with Prostate Cancer or other BRCA2-related diseases has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant using HDR assays, which has been recognized a gold standard by the ClinGen Sequence Variant Interpretation (SVI) working group (Guidugli_2018, Richardson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 29394989, 33609447). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA2)

-

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ile2821Thr variant has been reported once in the literature in an in silico study that used a computational method to determine the pathogenicity of various BRCA2 variants (the result was equivocal for this variant). However, since the number of proband or control chromosomes was not provided, the variant frequency in the general population cannot be determined (Karchin 2008). It is reported in the BIC database once, as a variant with no known clinical significance. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80359096) but no frequency information was provided and therefore is not very informative for assessing the population frequency. This residue is not conserved in mammals but computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSSUM) suggest that the p.Ile2821Thr variant may impact the protein. Furthermore, the p.Ile2821Thr variant occurs outside of the splicing consensus sequence but in-silico prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 5 different programs. This information is also not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29394989). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function. ClinVar contains an entry for this variant (Variation ID: 52595). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2821 of the BRCA2 protein (p.Ile2821Thr). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.61	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.67
MutPred		0.45		Loss of stability (P = 0.0496);Loss of stability (P = 0.0496);
MVP		0.94
MPC		0.11
ClinPred		0.94	D
GERP RS		5.2
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80359096; hg19: chr13-32944669;