Genetic Variant NM_024675.4:c.1A>G (chr16-23641157-T-C) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_024675.4(PALB2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALB2
NM_024675.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.67

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 17 pathogenic variants. Next in-frame start position is after 296 codons. Genomic position: 23635660. Lost 0.249 part of the original CDS.

PS1

Another start lost variant in NM_024675.4 (PALB2) was described as [Likely_pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-23641157-T-C is Pathogenic according to our data. Variant chr16-23641157-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 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.1A>G	p.Met1?	start_lost	Exon 1 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246052

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133830

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460488

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726466

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PALB2 mRNA. The next in-frame methionine is located at codon 296. This variant is present in population databases (no rsID available, gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with bile duct cancer, breast cancer, glioblastoma multiforme, and/or pancreatic cancer (PMID: 29625052, 31173646, 31263571, 31871297). ClinVar contains an entry for this variant (Variation ID: 246182). If translation initiation is rescued by the downstream methionine at codon 296, this would result in loss of the coiled-coil domain (p.Leu9-Glu42) of the PALB2 protein, which is critical for the interaction between BRCA1/BRCA2, and necessary for homology-directed DNA repair (PMID: 16793542, 19369211, 26649820, 25099575). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Leu35Pro) have been determined to be pathogenic (PMID: 28319063, 30337689, 31586400). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 06, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 07, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the PALB2 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was identified in an individual with a personal history of breast cancer as part of a large Canadian cohort study of 2870 individuals Bhai et al. Front Genet. 2021 Jul;12:698595). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Oct 26, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the loss of the translation initiation codon (methionine at codon 1) of the PALB2 gene. This variant is expected to disrupt the expression of the full-length PALB2 protein. If the next in-frame methionine at codon 296 is used as an alternate translation initiation codon, the resulting protein would be 25% shorter than the wild type protein and lack the coiled-coil domain (p.Leu9-Glu42) that mediates the interaction between PALB2 and BRCA1 (PMID: 19369211, 25099575) and, therefore, is critical for homology-directed repair (PMID: 16793542, 19369211). Although, to our knowledge, functional studies have not been reported for this variant, it is expected to disrupt PALB2 protein function. This variant has not been reported in individuals affected with hereditary cancer in the literature, but two different nucleotide substitution variants affecting the translation initiator methionine have been identified in individuals with breast and pancreatic cancer (PMID: 31173646, 31871297). This variant has been identified in 1/246052 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Sep 10, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal and/or family history of breast and other cancers (PMID: 34326862, 28779002); This variant is associated with the following publications: (PMID: 28779002, 34326862) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.99

MetaSVM

Benign

-0.93

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.30

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.99

Loss of glycosylation at P5 (P = 0.2047);

MVP

0.70

ClinPred

0.97

GERP RS

5.1

Varity_R

0.60

gMVP

0.046

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