rs879254144

Positions:

• chr16-23641157-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The ENST00000261584.9(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 ENST00000261584.9 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.67

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000261584.9 (PALB2) was described as [Pathogenic] in ClinVar as 1801543
• 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/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1A>G	p.Met1?	start_lost	1/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1A>G	p.Met1?	start_lost	1/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246052 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133830

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: 2 AN: 1460488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726466

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 26, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2024	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. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 06, 2023	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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2024

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	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.99		Loss of glycosylation at P5 (P = 0.2047);
MVP		0.70
ClinPred		0.97	D
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

Other links and lift over

dbSNP: rs879254144; hg19: chr16-23652478;