NM_024675.4(PALB2):c.3543del (p.Phe1181fs) AND Familial cancer of breast

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 1, 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:: RCV001215283.10

Allele description

NM_024675.4(PALB2):c.3543del (p.Phe1181fs)

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.3543del (p.Phe1181fs)

Other names:

NM_024675.4(PALB2):c.3543del; p.Phe1181fs

HGVS:

NC_000016.10:g.23603479del
NG_007406.1:g.42881del
NM_024675.4:c.3543delMANE SELECT
NP_078951.2:p.Phe1181fs
LRG_308t1:c.3543del
LRG_308:g.42881del
NC_000016.9:g.23614798del
NC_000016.9:g.23614800del
NM_024675.3:c.3543del

Protein change:

F1181fs

Links:

dbSNP: rs1567204928

NCBI 1000 Genomes Browser:

rs1567204928

Molecular consequence:

NM_024675.4:c.3543del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
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
SCV001387019	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003915582	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)	Uncertain significance (Jun 1, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001387019

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 7, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003915582

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)

Uncertain significance
(Jun 1, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001387019.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the PALB2 protein. Other variant(s) that disrupt this region (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671, 20927582, 26283626, 26296701). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with PALB2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PALB2 gene (p.Phe1181Leufs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acids of the PALB2 protein.

#	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, SCV003915582.2

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

Description

The c.3543del (p.Phe1181fs) variant in PALB2 is a frameshift variant predicted to alter a region that is critical to protein function. The C-terminal end of the WD40 domain is substituted by an alternative extended sequence. This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as variant of uncertain significance 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_Strong, PM2_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

Last Updated: Sep 8, 2024

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