13-32326581-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_000059.4(BRCA2):c.599C>T(p.Thr200Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,611,452 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. TP200TLT) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 5.30

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40088344).

BP6

Variant 13-32326581-C-T is Benign according to our data. Variant chr13-32326581-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140966.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.599C>T	p.Thr200Ile	missense_variant	Exon 7 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.599C>T	p.Thr200Ile	missense_variant	Exon 7 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.230C>T	p.Thr77Ile	missense_variant	Exon 7 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.599C>T		non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459238

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Apr 29, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of breast and other cancers (Yang 2017, Maillet 2006, Quiles 2016, Zuntini 2018, Santonocito 2020, Vietri 2021); Published functional studies demonstrate retained homology directed repair activity, ability to rescue cell lethality, and discordant results with respect to splicing (Mesman 2018, Quiles 2016, Di Giacomo 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 827C>T; This variant is associated with the following publications: (PMID: 33484353, 32438681, 30254663, 29988080, 28664506, 22144684, 16875939, 21702907, 26913838, 26780556, 26269718, 23983145) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.599C>T (p.Thr200Ile) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 16875939 (2006), 26780556 (2016), 28664506 (2017), 30254663 (2018), 32438681 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 33484353 (2021)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMID: 29988080 (2018), 23983145 (2013), 26780556 (2016)). The frequency of this variant in the general population, 0.000004 (1/251382 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Mar 05, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 20, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS3 c.599C>T located in exon 7 of the BRCA2 gene, is predicted to result in the substitution of threonine by isoleucine at codon 200, p.(Thr200Ile).This position is outside a (potentially) clinically important functional domain but the SpliceAI algorithm results in a non-informative deltascore (0.15) for the effect of this variant on splicing. This variant is found in 1/236844 in the gnomAD v2.1.1 database, exome non-cancer data set. This variant has been reported in the ClinVar database (3x uncertain significance, 5x likely benign) in the LOVD database (2x uncertain significance, 1x not classified) and in BRCA Exchange database as not yet reviewed. Results from one calibrated study with cDNA based design not considered for code application (PMID:32444794). Reported by one calibrated study incorporating mRNA splicing effect to affect function similar to benign control variants (PMID:29988080) (BS3). Based on currently available information, the variant c.599C>T is classified as a likely benign variant according to ClinGen-BRCA1 and BRCA2 Guidelines version 1.0.0. -

Mar 04, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with isoleucine at codon 200 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant does not impact BRCA2 protein in homology-directed repair and cisplatin sensitivity assays in Brca2-deficient mouse embryonic stem cells (PMID 29988080). RNA studies have reported partial to no impact on splicing, resulting in the out-of-frame skipping of exon 7 (PMID: 23983145, 26780556). This variant has been detected in at least three individuals affected with breast cancer and in an individual affected with endometrial cancer (PMID: 33471991, 33484353; Leiden Open Variation Database DB-ID BRCA2_000713; Color internal data). This variant has been identified in 1/251382 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Feb 20, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition

Uncertain:1

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with isoleucine at codon 200 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 protein in homology-directed repair and cisplatin sensitivity assays in Brca2-deficient mouse embryonic stem cells (PMID 29988080). RNA studies have reported partial to no impact on splicing, resulting in the out-of-frame skipping of exon 7 (PMID: 23983145, 26780556). This variant has been detected in at least three individuals affected with breast cancer and in an individual affected with endometrial cancer (PMID: 33471991, 33484353; Leiden Open Variation Database DB-ID BRCA2_000713; Color internal data). This variant has been identified in 1/251382 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Jun 10, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.599C>T (p.Thr200Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.599C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.2774_2775delCT, p.Ser925TyrfsX10), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Quiles_2016, Mesman_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=3, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:1

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BS1(Supporting)+BS3(Strong)+BP5(Supporting) 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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-1.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Vest4

0.48

MutPred

0.16

Loss of glycosylation at T200 (P = 0.023);Loss of glycosylation at T200 (P = 0.023);

MVP

0.93

MPC

0.17

ClinPred

0.97

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over