chr16-23641140-C-A

Position:

• chr16-23641140-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.18G>T​(p.Gly6Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 0.727

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23641140-C-A is Pathogenic according to our data. Variant chr16-23641140-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23641140-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.18G>T	p.Gly6Gly	synonymous_variant	1/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.18G>T	p.Gly6Gly	synonymous_variant	1/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2023	Exonic variant demonstrated to result in aberrant splicing leading to a predicted null allele in a gene for which loss-of-function is a known mechanism of disease (PMID: 30255452); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29522266, 30441849, 32728620, 30255452) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 24, 2023	The PALB2 c.18G>T (p.Gly6=) synonymous variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (http://gnomad.broadinstitute.org)). In the published literature, this variant has been identified in individuals with breast and ovarian cancer (PMIDs: 32728620 (2020), 30441849 (2018), 29522266 (2018)), and to segregate with disease in a family with pancreatic, thyroid, and breast cancer (PMID: 30255452 (2019)). Experimental studies indicated this variant disrupted PALB2 mRNA splicing, resulting in a frameshift and premature termination of PALB2 protein synthesis (PMID: 30255452 (2019)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 19, 2022	- -

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change affects codon 6 of the PALB2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with pancreatic, thyroid, and/or breast cancer (PMID: 30255452, 32728620). ClinVar contains an entry for this variant (Variation ID: 142432). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 30255452; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 05, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center	Dec 14, 2018	Experimental study demonstrated that this variant leads to aberrant splicing and deletion of the 3' end of exon 1. It is predicted to lead to a truncated or absent protein (PMID: 30255452). This variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 27, 2024	The c.18G>T variant (also known as p.G6G), located in coding exon 1, results from a G to T substitution at nucleotide position 18 of the PALB2 gene. This nucleotide substitution does not change the amino acid at codon 6. This alteration was identified in a patient with thyroid cancer at 25 and pancreatic cancer at 55, and a family history of breast and pancreatic cancer (Yang C et al. Breast Cancer Res. Treat. 2018 Sep; Epub ahead of print). This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358) and in a woman with breast cancer diagnosed at age 31 (Kuemmel S et al. NPJ Breast Cancer. 2020 Jul;6:31). RNA analyses have shown that this alteration creates a cryptic splice donor site resulting in a deletion of part of exon 1, a reading frame shift, and a premature stop codon (p.G6Vfs*26) (Yang C et al. Breast Cancer Res. Treat. 2018 Sep; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2022	This synonymous variant causes a G>T nucleotide change in exon 1 of the PALB2 gene. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 31 nucleotides upstream of the native intron 1 splice donor site. A functional RNA study has shown that this cryptic donor site is used, resulting in a complete disruption of normal splicing in the mutant allele (PMID: 30255452). Among several abnormal transcripts produced from the mutant allele, the major abnormal transcript resulted in a deletion of 32 base pairs in exon 1 and frameshift (r.17_48del; p.Gly6Valfs*26). This variant was observed in an individual affected with pancreatic and thyroid cancers at 55 and 25 years old, respectively, with family history of breast, pancreatic and other cancers in multiple relatives (PMID: 30255452). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 14, 2022

Variant summary: PALB2 c.18G>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a novel exonic 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to a deletion of 32 base pairs in exon 1, which leads to a frameshift and truncated protein (Yang_2019). The variant was absent in 247932 control chromosomes. c.18G>T has been reported in the literature as a VUS in an individual from a cohort of unselected individuals with Ovarian Cancer (Koczkowska_2018), in a proband with pancreatic and throid cancers and a family history of pancreatic and breast cancers (Yang_2019) and in a woman with ER+/PR+/HER2- high grade invasive breast cancer concurrent with ductal carcinoma in situ (DCIS) (Kuemmel_2020). These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=3; VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 2
DS_DL_spliceai		0.92		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782462; hg19: chr16-23652461;