16-23637932-C-G

Position:

• chr16-23637932-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024675.4(PALB2):​c.129G>C​(p.Lys43Asn) 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. 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. K43E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.596

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14966416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.129G>C	p.Lys43Asn	missense_variant	3/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.129G>C	p.Lys43Asn	missense_variant	3/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2021

The p.K43N variant (also known as c.129G>C), located in coding exon 3 of the PALB2 gene, results from a G to C substitution at nucleotide position 129. The lysine at codon 43 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.028
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.016	D;.
Polyphen		0.36	B;.
Vest4		0.28
MutPred		0.16		Loss of methylation at K43 (P = 0.0211);.;
MVP		0.69
MPC		0.37
ClinPred		0.91	D
GERP RS		2.3
Varity_R		0.21
gMVP		0.058

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23649253;