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

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:
RCV001215283.11

Allele description [Variation Report for NM_024675.4(PALB2):c.3543del (p.Phe1181fs)]

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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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001387019Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 7, 2019) 		germlineclinical testing

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

SCV003915582ClinGen 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) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001387019.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV003915582.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot 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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024