GeneBe

rs180177132

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_024675.4(PALB2):​c.3113G>C​(p.Trp1038Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PALB2
NM_024675.4 missense, splice_region

Scores

6
7
6
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.74
Variant links:
Genes affected
PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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 16-23621362-C-G is Pathogenic according to our data. Variant chr16-23621362-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2673836.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.3113G>C p.Trp1038Ser missense_variant, splice_region_variant Exon 10 of 13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.3113G>C p.Trp1038Ser missense_variant, splice_region_variant Exon 10 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial cancer of breast Pathogenic:1
Sep 14, 2023
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
34
DANN
Benign
0.97
DEOGEN2
Benign
0.15
T;T
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.85
T;T
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.1
.;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-12
D;D
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.91
MutPred
0.73
.;Loss of sheet (P = 0.007);
MVP
0.76
MPC
0.41
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.28
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.22
Position offset: 31
DS_DL_spliceai
0.28
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23632683; API