NM_024675.4(PALB2):c.3362del (p.Gly1121fs) AND Familial cancer of breast

Germline classification:: Likely pathogenic (9 submissions)
Last evaluated:: Apr 5, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000114624.28

Allele description [Variation Report for NM_024675.4(PALB2):c.3362del (p.Gly1121fs)]

NM_024675.4(PALB2):c.3362del (p.Gly1121fs)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.3362del (p.Gly1121fs)

Other names:

NM_024675.3(PALB2):c.3362del; p.Gly1121fs

HGVS:

NC_000016.10:g.23603659del
NG_007406.1:g.42700del
NM_024675.4:c.3362delMANE SELECT
NP_078951.2:p.Gly1121fs
LRG_308:g.42700del
NC_000016.10:g.23603658delC
NC_000016.9:g.23614979del
NC_000016.9:g.23614980del
NM_024675.3:c.3362delG
NM_024675.4:c.3362del
p.G1121VFS*3

Links:

dbSNP: rs515726117

NCBI 1000 Genomes Browser:

rs515726117

Molecular consequence:

NM_024675.4:c.3362del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000219007	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 23935836, 24136930, 24549055, 26283626, 17200668, 17200671, 21365267, 25099575, 25452441, 26315354, 28492532
SCV000267974	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	criteria provided, single submitter (Thompson et al. (Breast Cancer Res. 2015))	Likely pathogenic (Jun 1, 2015)	germline	case-control	PubMed (1) [See all records that cite this PMID]
SCV001193402	Leiden Open Variation Database	no assertion criteria provided	Pathogenic (May 13, 2019)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 23935836, 24136930, 24549055, 25099575, 25452441
SCV001440263	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002499076	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003915567	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HBOP VCEP ACMG Specifications PALB2 V1.0.0)	Likely pathogenic (Apr 5, 2023)	germline	curation	Citation Link,
SCV004188485	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Sep 15, 2023)	unknown	clinical testing	Citation Link,
SCV004202114	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848615	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Mar 23, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 24136930, 34399810, 25452441, 26283626, 24549055, 29431189, 31636395, 23935836, 31447099, 32853339, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1996	not provided	curation, case-control
not provided	germline	no	1	not provided	not provided	1998	not provided	case-control
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.

Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D; Breast Cancer Susceptibility Collaboration (UK)., Easton DF, Stratton MR.

Nat Genet. 2007 Feb;39(2):165-7. Epub 2006 Dec 31.

PubMed [citation]

PMID:: 17200668
PMCID:: PMC2871593

Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.

Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, Wurm M, Batish SD, Lach FP, Yetgin S, Neitzel H, Ariffin H, Tischkowitz M, Mathew CG, Auerbach AD, Rahman N.

Nat Genet. 2007 Feb;39(2):162-4. Epub 2006 Dec 31.

PubMed [citation]

PMID:: 17200671

See all PubMed Citations (17)

Details of each submission

From Invitae, SCV000219007.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change creates a premature translational stop signal (p.Gly1121Valfs*3) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the PALB2 protein. This variant is present in population databases (rs515726117, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 23935836, 24136930, 24549055, 25099575, 26283626; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126739). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Leu1143Thrfs*14 and p.Tyr1183*) have been determined to be pathogenic (PMID: 17200668, 17200671, 21365267, 25099575, 25452441, 26315354; Invitae). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, SCV000267974.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	case-control	PubMed (1)
2	not provided	1	not provided	not provided	case-control	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1996	not provided	not provided		1	not provided	not provided	not provided
2	germline	no	1998	not provided	not provided		1	not provided	not provided	not provided

From Leiden Open Variation Database, SCV001193402.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440263.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002499076.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1, PS3, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV003915567.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.3362del (p.Gly1121fs) variant in PALB2 is a frameshift 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 1123-1187) in a gene where loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000003979 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified 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, PM5_Supporting)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004188485.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004202114.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848615.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Gly1121ValfsX3 variant in PALB2 has been reported in at least 8 individuals with breast cancer, including 2 siblings with a family history of PALB2-associated cancers (Blanco 2013 PMID: 23935836, Janatova 2013 PMID: 24136930, Castera 2014 PMID: 24549055, Antoniou 2014 PMID: 25099575, Thompson 2015 PMID: 26283626, Couch 2015 PMID: 25452441, Lee 2018 PMID: 29431189) and has also been reported by other clinical laboratories in ClinVar (Variation ID 126739). It was identified in 0.001% (1/67996) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1121 and leads to a premature termination codon 3 amino acids downstream. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~5% of the coding region, with 62 amino acids removed. However, these terminal amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver 2009 PMID: 19609323). In addition, several downstream truncating variants, have been observed in individuals with PALB2-related cancers and Fanconi anemia, supporting the functional importance of the last exon. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant PALB2-associated breast cancer. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1_Strong.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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