rs1290624507

chr16-23637924-T-C

Variant summary

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

The NM_024675.4(PALB2):c.137A>G(p.His46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. H46Y) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.322

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]

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=0.071933955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.137A>G	p.His46Arg	missense_variant	3/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.137A>G	p.His46Arg	missense_variant	3/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 46 of the PALB2 protein (p.His46Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 530102). 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 tolerated. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2020

Not observed at a significant frequency in large population cohorts (Lek 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The p.H46R variant (also known as c.137A>G), located in coding exon 3 of the PALB2 gene, results from an A to G substitution at nucleotide position 137. The histidine at codon 46 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly 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	0.079
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Benign	0.91
DEOGEN2	Benign	0.099	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	N;.
REVEL	Benign	0.034
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.032	D;.
Polyphen		0.15	B;.
Vest4		0.28
MutPred		0.13		Loss of ubiquitination at K50 (P = 0.022);.;
MVP		0.46
MPC		0.068
ClinPred		0.10	T
GERP RS		2.2
Varity_R		0.054
gMVP		0.020

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

LitVar

Other links and lift over

dbSNP: rs1290624507; hg19: chr16-23649245;