ENST00000568219.5:c.-326C>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The ENST00000568219.5(PALB2):c.-326C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PALB2
ENST00000568219.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 1.91

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0695166).

BP6

Variant 16-23635986-G-T is Benign according to our data. Variant chr16-23635986-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 481010.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.560C>A	p.Pro187His	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.560C>A	p.Pro187His	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251428

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727242

show subpopulations

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:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: BP4 supporting -

Breast-ovarian cancer, familial, susceptibility to, 5

Uncertain:2

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.560C>A (p.Pro187His) variant in PALB2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro187His variant has allele frequency 0.006% is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely benign / Uncertain Significance. The amino acid change p.Pro187His in PALB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 187 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Oct 28, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Mar 17, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer or Fanconi anemia (George et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 20871615, 19369211, 35264596, 34585473, 30949167) -

Jun 15, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

May 19, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.45

M_CAP

Benign

0.051

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.58

Vest4

0.22

MutPred

0.12

Loss of glycosylation at P187 (P = 0.0589);

MVP

0.57

MPC

0.36

ClinPred

0.71

GERP RS

4.2

Varity_R

0.14

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over