rs377471435

Positions:

chr13-32346914-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000059.4(BRCA2):c.7007+18T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,587,582 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0980

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:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 13-32346914-T-A is Benign according to our data. Variant chr13-32346914-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 219852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7007+18T>A		intron_variant		ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7007+18T>A	intron_variant	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.6638+18T>A	intron_variant	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.7007+18T>A	intron_variant	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000736

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243612

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131820

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:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1435458

Hom.:

Cov.:

AF XY:

0.0000420

AC XY:

AN XY:

714974

show subpopulations

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:

0.0000577

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000227

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	Variant summary: BRCA2 c.7007+18T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 243612 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7007+18T>A has been reported in the literature in a study of patients affected with breast and/or ovarian cancer (e.g. Caux-Moncoutier_2011) without evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Nov 07, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 01, 2016

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.4

DANN

Benign

0.63

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