chr16-23630285-C-G

Position:

• chr16-23630285-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024675.4(PALB2):​c.1869G>C​(p.Lys623Asn) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.104

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30580944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1869G>C	p.Lys623Asn	missense_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1869G>C	p.Lys623Asn	missense_variant	5/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 07, 2019	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PALB2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 623 of the PALB2 protein (p.Lys623Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	.;D
Vest4		0.44
MutPred		0.43		.;Loss of ubiquitination at K623 (P = 0.0051);
MVP		0.63
MPC		0.36
ClinPred		1.0	D
GERP RS		-0.45
Varity_R		0.49
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555460612; hg19: chr16-23641606;