rs180177115

Positions:

• chr16-23629231-G-A
• chr16-23629231-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM5_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.2559C>T (p.Gly853=) variant is a synonymous (silent) variant in PALB2. This variant has a minor allele frequency in gnomAD of 0.00001758 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This alteration is observed to introduce a cryptic splice site causing a 29 base pair deletion in exon 6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID:31843900, 32133419). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM5_supporting criteria) LINK:https://erepo.genome.network/evrepo/ui/classification/CA269540/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 0.0580

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2559C>T	p.Gly853=	synonymous_variant	6/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2559C>T	p.Gly853=	synonymous_variant	6/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461296 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726990

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 22, 2022	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.2559C>T (p.Gly853=) variant is a synonymous (silent) variant in PALB2. This variant has a minor allele frequency in gnomAD of 0.00001758 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This alteration is observed to introduce a cryptic splice site causing a 29 base pair deletion in exon 6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 31843900, 32133419). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM5_supporting criteria) -
Likely pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 31, 2022	_x000D_ Criteria applied: PS3, PS4_MOD, PM2_SUP, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 13, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change affects codon 853 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 present in population databases (rs180177115, gnomAD 0.002%). This variant has been observed in individual(s) with pancreatic cancer and breast cancer (PMID: 21285249, 26681312, 30426508). ClinVar contains an entry for this variant (Variation ID: 126660). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21285249, 31642931, 31843900; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Exonic variant demonstrated to cause a near-complete splice defect leading to a predicted null allele in a gene for which loss-of-function is a known mechanism of disease (Casadei et al., 2019; Karam et al., 2019; Landrith et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Identified in individuals with breast cancer (Casadei et al., 2011; Schubert et al., 2019); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26681312, 22692731, 33471991, 24870022, 23935381, 21285249, 32133419, 31642931, 25525159, 31843900, 30426508, 30255452, 32853339) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 17, 2021	This synonymous variant is predicted to activate a cryptic splice donor site located 29 nucleotides upstream of the reference splice site. RNA studies have shown the use of this cryptic splice donor site, leading to a deletion of 29 nucleotides at the end of exon 6 (PMID: 21285249, 31843900, 32133419). As a result, this variant creates a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product (PMID: 31843900). This variant has been reported in individuals affected with breast cancer (PMID: 21285249, 30426508) and pancreatic cancer (PMID: 26681312) in the literature. This variant has also been identified in 2/251262 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 29, 2024	The c.2559C>T pathogenic mutation (also known as p.G853G), located in coding exon 6 of the PALB2 gene, results from a C to T substitution at nucleotide position 2559. This nucleotide substitution does not change the amino acid glycine at codon 853. This alteration was identified in a patient with bilateral breast cancer (Schubert S et al. Int. J. Cancer. 2019 Jun 1;144(11):2683-2694). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel in a patient with pancreatic cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). Additionally, this variant was observed in a patient with invasive breast cancer with a history of invasive breast cancer in at least two close relatives. Analysis of the mutant transcripts showed that c.2559C>T creates a novel donor site causing a frameshift deletion of 29 base pairs in coding exon 6 (Casadei S et al. Cancer Res. 2011 Mar 15;71(6):2222-9). Quantitative RNA studies showed that 98% of transcripts produced by c.2559C>T variant were abnormal (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec). 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. Multiple internal RNA assays confirm that c.2559C>T results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	19
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 2
DS_DL_spliceai		0.81		Position offset: -27

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177115; hg19: chr16-23640552;