rs80358985

Positions:

chr13-32356557-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBP6

The NM_000059.4(BRCA2):c.7565C>T(p.Ser2522Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S2522S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 4.14

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 Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

BP6

Variant 13-32356557-C-T is Benign according to our data. Variant chr13-32356557-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38104.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7565C>T	p.Ser2522Phe	missense_variant	15/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7565C>T	p.Ser2522Phe	missense_variant	15/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251136

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135734

show subpopulations

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	This variant is associated with the following publications: (PMID: 21120943, 11873550, 19043619, 25782689, 15944772, 19471317, 24504028, 24556621, 29394989, 29884841) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 15944772 (2005), 33471991 (2021)), ovarian cancer (PMID: 24504028 (2014)), and prostate cancer (PMID: 24556621 (2014)). Functional studies indicated that this variant does not disrupt the homology-directed DNA repair function of the BRCA2 protein (PMIDs: 29394989 (2018), 29884841 (2019), 35736817 (2022)). The frequency of this variant in the general population, 0.0000071 (2/282548 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2017	Variant summary: The BRCA2 c.7565C>T (p.Ser2522Phe) variant located in the helical domain (Salgado_2005) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/120720 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of co-occurrence and/or cosegregation data). In addition, multiple clinical diagnostic laboratories cite the variant with conflicting classifications "likely benign" or "uncertain significance." Therefore, due to the limited available information, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies). -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 27, 2012	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 25, 2020	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	Jun 21, 2018	- -

Chordoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Integrative Tumor Epidemiology Branch, National Institutes of Health

Mar 22, 2021

No impact on ES cell survival or drug sensitivity (no impact on BRCA2 function) -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.80

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0050

D;D

Vest4

0.78

MutPred

0.87

Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);

MVP

0.97

MPC

0.17

ClinPred

0.91

GERP RS

5.5

gMVP

0.57

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

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