chr16-23603471-G-T

Position:

• chr16-23603471-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM3_Strong PP1_Strong PVS1

This summary comes from the ClinGen Evidence Repository: The c.3549C>A (p.Tyr1183Ter) variant in PALB2 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1183-1186) in a gene where loss-of-function is an established disease mechanism. This variant, or another variant leading to the same protein truncation, has been detected in three individuals with autosomal recessive FANCN. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and three of those were confirmed in trans by parental testing (co-occurring variants: c.2257C>T (p.Arg753Ter); c.2962C>T (p.Gln988Ter); c.3116delA (p.Asn1039Ilefs*2): PMID 17200671). The variant has been reported to segregate with breast and/or pancreatic cancer in 15 affected members from 6 families (Invitae; Ambry Genetics). This variant is non-functional in multiple different protein assays (PMID 31757951, PMID 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. In summary, this variant meets the criteria to be classified as 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, PP1_Strong, PM3_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA288488/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:23
• Conservation: PhyloP100: 0.163

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 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.3549C>A	p.Tyr1183Ter	stop_gained	13/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3549C>A	p.Tyr1183Ter	stop_gained	13/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251420 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1459920 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726434

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2022	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Reported in multiple individuals with PALB2-related cancers (Rahman 2007, Ding 2011, Hofstatter 2011, Antoniou 2014, Ellingson 2015, Ramus 2015).; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26296701, 19763819, 26596371, 27356891, 21618343, 21365267, 20927582, 28873162, 19584259, 17200671, 25225577, 18053174, 21153565, 18302019, 23935381, 19609323, 17200668, 21165770, 26315354, 19464302, 24998779, 25099575, 26681312, 26641009, 24728327, 28008555, 29387807, 28152038, 26283626, 19264984, 29785153, 31948886, 32546565, 31589614, 33403473, 33882707, 33420229) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 05, 2021	PS3, PS4, PM2, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 01, 2018	The PALB2 c.3549C>A; p.Tyr1183Ter variant (rs118203998) is described in individuals and families affected with breast cancer, ovarian cancer and pancreatic cancer; and in Fanconi anemia when paired with another pathogenic variant on the opposite chromosome (Hoffstatter 2011, Reid 2007, Susswein 2016). This variant removes four amino acids thought to be critical in the protein structure, which may destabilize the protein (Oliver 2009). In support of this theory, cells derived from individuals harboring this variant and another truncation variant on the opposite chromosome do not produce PALB2 protein (Reid 2007). The variant is listed in the ClinVar database (Variation ID: 128144). The variant is also listed in the Genome Aggregation Database in 1 out of 246208 alleles. Considering available information, this variant is classified as pathogenic. Pathogenic PALB2 variants increase susceptibility to breast and pancreatic cancer (OMIM#601355). References: Hofstatter EW et al. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011 Jun;10(2):225-31. Oliver AW et al. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009 Sep;10(9):990-6. Reid S et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007 Feb;39(2):162-4. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 27, 2020	This nonsense variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast, ovarian and pancreatic cancer in the published literature (PMID: 26681312 (2015), 26315354 (2015), 26296701 (2015), 25099575 (2014), 21365267 (2011), 19264984 (2009)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -

Familial cancer of breast Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 23, 2023	Criteria applied: PVS1, PS1_MOD, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Tyr1183*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the PALB2 protein. This variant is present in population databases (rs118203998, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and Fanconi anemia (PMID: 17200671, 20927582, 21165770, 21365267, 26283626, 26296701). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 128144). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PALB2 function (PMID: 17200671, 19609323, 31757951). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.3549C>A (p.Tyr1183Ter) variant in PALB2 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1183-1186) in a gene where loss-of-function is an established disease mechanism. This variant, or another variant leading to the same protein truncation, has been detected in three individuals with autosomal recessive FANCN. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and three of those were confirmed in trans by parental testing (co-occurring variants: c.2257C>T (p.Arg753Ter); c.2962C>T (p.Gln988Ter); c.3116delA (p.Asn1039Ilefs*2): PMID 17200671). The variant has been reported to segregate with breast and/or pancreatic cancer in 15 affected members from 6 families (Invitae; Ambry Genetics). This variant is non-functional in multiple different protein assays (PMID 31757951, PMID 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. In summary, this variant meets the criteria to be classified as 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, PP1_Strong, PM3_Strong) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2022	The p.Y1183* pathogenic mutation (also known as c.3549C>A), located in coding exon 13 of the PALB2 gene, results from a C to A substitution at nucleotide position 3549. This changes the amino acid from a tyrosine to a stop codon within exon 13. This alteration occurs at the 3' terminus of PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last four amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). The p.Y1183* mutation has been identified with a PALB2 pathogenic variant in multiple individuals with clinical features of Fanconi Anemia-N (FA-N) (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). Lymphoblastoid cells from at least one of these patients was found to have no detectable PALB2 protein (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). Truncations at this position have been reported in multiple familial breast cancer kindreds to date (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Hofstatter EW et al. Fam. Cancer. 2011 Jun;10:225-31; Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). This alteration was also identified in 4/10030 consecutive breast cancer patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal. Functional studies have shown that the PALB2 protein is not detectable in a carrier of this variant (PMID: 17200671) and is predicted to disrupt the BRCA2/RAD51 binding domain (PMID: 19609323). This variant has been reported in over ten individuals affected with breast or ovarian cancer (PMID: 20927582, 25099575, 26296701, 26315354, 26681312, 26641009). This variant (c.3549C>A) and a different nucleotide change resulting in the same protein consequence (c.3549C>G) have been observed in three individuals diagnosed with Fanconi anemia who also carried different pathogenic variants in the same gene (PMID: 17200671). This variant has been identified in 1/251420 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 Pathogenic. -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

PALB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

The PALB2 c.3549C>A variant is predicted to result in premature protein termination (p.Tyr1183*). This variant has been reported in multiple individuals with breast, ovarian, or pancreatic cancer (Churpek et al. 2015. PubMed ID: 26641009; Hofstatter et al. 2011. PubMed ID: 21365267; Table S1, Susswein et al. 2015. PubMed ID: 26681312). This variant removes the last four C-terminal amino acids from the protein and is thought to contribute to protein destabilization (Oliver et al. 2009. PubMed ID: 19609323). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been interpreted by multiple laboratories as pathogenic in ClinVar, as well as the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/128144/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Dec 28, 2023

Criteria applied: PVS1,PS1,PS4 -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 05, 2019

Variant summary: PALB2 c.3549C>A (p.Tyr1183X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-06 in 258634 control chromosomes. c.3549C>A has been well reported in the literature in multiple individuals affected with several cancer phenotypes such as, epithelial ovarian cancer (Ramus_2015), in bi allelic PALB2 mediated Fanconi anemia (with p.R753*, Reid_2007), breast and pancreatic cancer (Hofstatter_2011), and male breast cancer (Ding_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no detectable PALB2 protein in lymphoblastoid cells of a patient with the Fanconi anemia phenotype, thereby confirming the null allele outcome for this variant (Reid_2007). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	0.98
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.12	N
MutationTaster	Benign	1.0	D
Vest4		0.75
GERP RS		-0.82

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: rs118203998; hg19: chr16-23614792; COSMIC: COSV104552896; COSMIC: COSV104552896;