Genetic Variant PALB2:p.Pro4Ala (chr16-23641148-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_024675.4(PALB2):c.10C>G(p.Pro4Ala) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

0 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 links:

DCTN5 (HGNC:24594): (dynactin subunit 5) This gene encodes a subunit of dynactin, a component of the cytoplasmic dynein motor machinery involved in minus-end-directed transport. The encoded protein is a component of the pointed-end subcomplex and is thought to bind membranous cargo. A pseudogene of this gene is located on the long arm of chromosome 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

DCTN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 25 uncertain in NM_024675.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09497416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	NM_024675.4	MANE Select	c.10C>G	p.Pro4Ala	missense	Exon 1 of 13	NP_078951.2
PALB2	NM_001407296.1		c.10C>G	p.Pro4Ala	missense	Exon 1 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.10C>G	p.Pro4Ala	missense	Exon 1 of 12	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.10C>G	p.Pro4Ala	missense	Exon 1 of 13	ENSP00000261584.4	Q86YC2
PALB2	ENST00000568219.5	TSL:1	c.-859C>G		5_prime_UTR	Exon 1 of 13	ENSP00000454703.2	H3BN63
PALB2	ENST00000970391.1		c.10C>G	p.Pro4Ala	missense	Exon 1 of 12	ENSP00000640450.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.22

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.65

M_CAP

Benign

0.0083

MetaRNN

Benign

0.095

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

1.8

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.029

Sift

Benign

0.24

Sift4G

Benign

0.33

Polyphen

0.30

Vest4

0.20

MutPred

0.13

Loss of catalytic residue at P4 (P = 0.0412)

MVP

0.46

MPC

0.23

ClinPred

0.47

GERP RS

3.4

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.088

gMVP

0.031

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over