13-32326499-G-T

Position:

chr13-32326499-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

The NM_000059.4(BRCA2):c.517G>T(p.Gly173Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G173V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 0.9979

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 2.04

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 uncertain in NM_000059.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32326499-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 13-32326499-G-T is Pathogenic according to our data. Variant chr13-32326499-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51805.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr13-32326499-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.517G>T	p.Gly173Cys	missense_variant, splice_region_variant	7/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.517G>T	p.Gly173Cys	missense_variant, splice_region_variant	7/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449710

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2023	The c.517G>T variant (also known as p.G173C) is located in coding exon 6 of the BRCA2 gene. The glycine at codon 173 is replaced by cysteine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 6. This alteration has been observed in multiple breast and/or ovarian cancer cohorts from multiple ethnic backgrounds (Solano AR et al. Oncotarget, 2017 Sep;8:60487-60495; El Saghir NS et al. Oncologist, 2015 Apr;20:357-64; Kang E et al. Breast Cancer Res Treat, 2015 May;151:157-68). This nucleotide and amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. This alteration results in complete coding exon 6 skipping (also known as Exon 7 in the literature) in multiple minigene assays (Gaildrat P et al. J. Med. Genet. 2012 Oct;49:609-17; Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420). Another alteration impacting the same nucleotide position (c.517G>C) also causes the same splice defect (Ambry internal data; Baert A et al. Hum. Mutat. 2017 Dec). Yet another close-match alteration at this same acceptor site, BRCA2 c.517-2A>G, has been identified in a compound heterozygous and homozygous state in patients with Fanconi Anemia (Leach M et al. Practical Flow Cytometry in Hematology: 100 worked examples. 321-324; 2015; Muramatsu H et al. Genet. Med., 2017 07;19:796-802). BRCA2 c.517-2A>G also demonstrates an intermediate effect in a mouse embryonic stem cell survival and subsequent homology-directed DNA repair assays. Clinical and functional data collectively support BRCA2 c.517-2A>G as a likely hypomorphic variant (Mesman RLS et al. Genet Med, 2020 08;22:1355-1365). BRCA2 c.517-2A>G has a similar splice defect as this variant (Ambry internal data; Houdayer C et al. Hum Mut. 2012; 33:1228–38; Fraile-Bethencourt E et al. J. Pathol. 2019 08;248(4):409-420). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because a variant with a similar splicing profile as this variant is functionally hypomorphic and has been identified in multiple patients with Fanconi Anemia it may be similarly hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 11, 2023	This missense variant replaces glycine with cysteine at codon 173 of the BRCA2 protein. RNA studies using the mini-gene assay have reported that this variant affects RNA splicing and results in exon 7 skipping and protein truncation (PMID: 22962691, 30883759). A different variant occurring at the same nucleotide position, c.517G>C, has been shown to affect RNA splicing in cells derived from a carrier individual (PMID: 29280214), indicating that a change to the c.G nucleotide at this position impacts RNA splicing. This variant has been reported in multiple individuals affected with breast or ovarian cancer (PMID: 22962691, 25777348, 27463008, 28947987, 34072659; Color internal data; UMD database). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 30, 2016

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

Feb 26, 2013

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2023

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30883759). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 51805). This missense change has been observed in individual(s) with breast cancer (PMID: 22962691, 25777348, 28947987). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 173 of the BRCA2 protein (p.Gly173Cys). It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

0.65

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.092

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.070

T;T

Vest4

0.44

MutPred

0.28

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.92

MPC

0.17

ClinPred

0.92

GERP RS

4.6

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.40

Position offset: 0

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