rs1057517585

chr16-23641155-C-T

Variant summary

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

The NM_024675.4(PALB2):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,610 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: 6.8e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.95

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 NM_024675.4 (PALB2) was described as [Pathogenic] in ClinVar as 1801543
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23641155-C-T is Pathogenic according to our data. Variant chr16-23641155-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23641155-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3G>A	p.Met1?	start_lost	1/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3G>A	p.Met1?	start_lost	1/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460610 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726538

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 30, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 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 not present in population databases (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: 371919). 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	Counsyl	Aug 12, 2016	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2017	This variant alters the initiator Methionine codon, and the resultant protein would be described as“p.Met1?” to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein isproduced using an alternate Methionine codon. PALB2 c.3G>A has not been previously published as a pathogenicvariant, nor has it been reported as a benign polymorphism to our knowledge. As PALB2 c.3G>A is predicted to alternormal protein production, it is considered a likely pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

The p.M1? variant (also known as c.3G>A) is located in coding exon 1 of the PALB2 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This variant has been reported in an individual with metastatic pancreatic cancer diagnosed at 58 (Goldstein JB et al. Clin Cancer Res. 2020 Mar;26(6):1385-1394). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.29
Sift	Benign	0.040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0925);
MVP		0.73
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.60
gMVP		0.038

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057517585; hg19: chr16-23652476;