rs1555461462

Positions:

• chr16-23635473-G-A
• chr16-23635473-G-C
• chr16-23635473-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The ENST00000261584.9(PALB2):​c.1073C>T​(p.Pro358Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P358H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PALB2 ENST00000261584.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in ENST00000261584.9
• BP4: Computational evidence support a benign effect (MetaRNN=0.12695003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1073C>T	p.Pro358Leu	missense_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1073C>T	p.Pro358Leu	missense_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

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

Jan 07, 2019

The p.P358L variant (also known as c.1073C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 1073. The proline at codon 358 is replaced by leucine, an amino acid with similar properties. This amino acid position is not 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	0.089
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.24
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.078
Sift	Benign	0.083	T;T
Sift4G	Uncertain	0.026	D;D
Polyphen		0.93	.;P
Vest4		0.18
MutPred		0.18		.;Loss of methylation at K356 (P = 0.0851);
MVP		0.50
MPC		0.059
ClinPred		0.90	D
GERP RS		4.2
Varity_R		0.065
gMVP		0.20

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: rs1555461462; hg19: chr16-23646794; COSMIC: COSV55169000; COSMIC: COSV55169000;