16-23623129-C-G

Position:

• chr16-23623129-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024675.4(PALB2):​c.2836G>C​(p.Ala946Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A946G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Scores: Splicing: ADA: 0.1307
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0410

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2836G>C	p.Ala946Pro	missense_variant, splice_region_variant	9/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2836G>C	p.Ala946Pro	missense_variant, splice_region_variant	9/13	1	NM_024675.4	P1
	ENST00000561764.1	n.420-771C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2023

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 946 of the PALB2 protein (p.Ala946Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	0.74	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.23	T;T
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.44		.;Gain of relative solvent accessibility (P = 0.0215);
MVP		0.60
MPC		0.38
ClinPred		0.90	D
GERP RS		2.8
Varity_R		0.78
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.35
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23634450;