chr16-23638096-A-T

Position:

• chr16-23638096-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.82T>A variant in PALB2 is a missense variant predicted to cause substitution of tyrosine by asparagine at amino acid 28 (p.Tyr28Asn). This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (PM2_Supporting, BP1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16615316/MONDO:0016419/020

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 4.04

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.82T>A	p.Tyr28Asn	missense_variant	2/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.82T>A	p.Tyr28Asn	missense_variant	2/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 30, 2023	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 28 of the PALB2 protein (p.Tyr28Asn). 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. ClinVar contains an entry for this variant (Variation ID: 410148). 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.82T>A variant in PALB2 is a missense variant predicted to cause substitution of tyrosine by asparagine at amino acid 28 (p.Tyr28Asn). This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (PM2_Supporting, BP1). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2021

The p.Y28N variant (also known as c.82T>A), located in coding exon 2 of the PALB2 gene, results from a T to A substitution at nucleotide position 82. The tyrosine at codon 28 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.63	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.1	D;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.025	D;.
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.21		Loss of helix (P = 0.0104);.;
MVP		0.84
MPC		0.43
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.67
gMVP		0.28

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: rs1060502762; hg19: chr16-23649417;