rs763123300

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_000059.4(BRCA2):c.5028_5030del(p.Ser1676del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,594,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C1675C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.950

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5028_5030del	p.Ser1676del	inframe_deletion	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.5028_5030del	p.Ser1676del	inframe_deletion	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000423

AC:

AN:

236498

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128340

show subpopulations

Gnomad AFR exome

AF:

0.0000654

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442350

Hom.:

AF XY:

0.00000140

AC XY:

AN XY:

715354

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:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 5256_5258delTAG; This variant is associated with the following publications: (PMID: 9002670, 22193408) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 11, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 07, 2022	The c.5028_5030delTAG variant (also known as p.S1676del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame TAG deletion at nucleotide positions 5028 to 5030. This results in the in-frame deletion of a serine at codon 1676. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

May 01, 2012

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2022

This variant is present in population databases (rs763123300, gnomAD 0.007%). 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 and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 96814). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in BRCA2 in at least one individual (Invitae), which suggests that this variant may not be disease-causing. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant, c.5028_5030del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Ser1676del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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