NM_024675.4(PALB2):c.2289G>C (p.Leu763Phe) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jun 28, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000587948.16

Allele description [Variation Report for NM_024675.4(PALB2):c.2289G>C (p.Leu763Phe)]

NM_024675.4(PALB2):c.2289G>C (p.Leu763Phe)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.2289G>C (p.Leu763Phe)

Other names:

p.L763F:TTG>TTC

HGVS:

NC_000016.10:g.23629865C>G
NG_007406.1:g.16493G>C
NM_024675.4:c.2289G>CMANE SELECT
NP_078951.2:p.Leu763Phe
NP_078951.2:p.Leu763Phe
LRG_308t1:c.2289G>C
LRG_308:g.16493G>C
LRG_308p1:p.Leu763Phe
NC_000016.9:g.23641186C>G
NM_024675.3:c.2289G>C
p.L763F
p.Leu763Phe

Protein change:

L763F

Links:

dbSNP: rs373478248

NCBI 1000 Genomes Browser:

rs373478248

Molecular consequence:

NM_024675.4:c.2289G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211515	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Feb 18, 2021)	germline	clinical testing	Citation Link,
SCV001469845	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 28, 2023)	unknown	clinical testing	PubMed (15) [See all records that cite these PMIDs] 32068069, 31636395, 30093976, 30287823, 31843900, 28779002, 23977390, 25225064, 25186627, 26283626, 28825143, 30447919, 33471991, 26689913, 26467025
SCV001979720	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001980479	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002036174	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	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

Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel.

Kwong A, Shin VY, Chen J, Cheuk IWY, Ho CYS, Au CH, Chan KKL, Ngan HYS, Chan TL, Ford JM, Ma ESK.

J Mol Diagn. 2020 Apr;22(4):544-554. doi: 10.1016/j.jmoldx.2020.01.013. Epub 2020 Feb 15.

PubMed [citation]

PMID:: 32068069

Functional characterization of 84 PALB2 variants of uncertain significance.

Wiltshire T, Ducy M, Foo TK, Hu C, Lee KY, Belur Nagaraj A, Rodrigue A, Gomes TT, Simard J, Monteiro ANA, Xia B, Carvalho MA, Masson JY, Couch FJ.

Genet Med. 2020 Mar;22(3):622-632. doi: 10.1038/s41436-019-0682-z. Epub 2019 Oct 21.

PubMed [citation]

PMID:: 31636395
PMCID:: PMC7056643

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000211515.11

#	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 associated with the following publications: (PMID: 28678401, 26283626, 23977390, 26689913, 28825143, 28779002, 25186627, 25225064, 30287823, 29338689, 30093976, 30447919, 31636395)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469845.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

In the published literature, the variant has been reported in individuals with breast cancer as well as in healthy controls (PMID: 32068069 (2020), 30287823 (2018), 28825143 (2017), 26283626 (2015), 25186627 (2015), 23977390 (2013), 33471991 (2021) and LOVD (http://databases.lovd.nl/shared/genes/PALB2)). In addition, a functional study suggests that this variant is not damaging to the homology-directed DNA repair activity of PALB2, however, further studies are necessary to confirm this finding (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.0007 (14/19950 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001979720.1

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

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001980479.1

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

#	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 Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036174.1

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

#	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

Last Updated: Mar 16, 2024

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