chr16-23623096-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024675.4(PALB2):​c.2869A>G​(p.Lys957Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K957Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PALB2
NM_024675.4 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.36

Publications

1 publications found
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]
PALB2 Gene-Disease associations (from GenCC):
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
  • Fanconi anemia complementation group N
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
  • pancreatic cancer, susceptibility to, 3
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • familial ovarian cancer
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37065315).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.2869A>G p.Lys957Glu missense_variant Exon 9 of 13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.2869A>G p.Lys957Glu missense_variant Exon 9 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.028
T;T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.37
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
.;M
PhyloP100
2.4
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-2.4
N;D
REVEL
Benign
0.044
Sift
Benign
0.12
T;T
Sift4G
Uncertain
0.027
D;D
Polyphen
0.17
.;B
Vest4
0.61
MutPred
0.21
.;Loss of ubiquitination at K957 (P = 0.0067);
MVP
0.56
MPC
0.27
ClinPred
0.75
D
GERP RS
3.6
Varity_R
0.29
gMVP
0.45

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

Other links and lift over

dbSNP: rs515726103; hg19: chr16-23634417; API