NM_024675.4(PALB2):c.13C>T (p.Pro5Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jul 1, 2024
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:: RCV000589509.25

Allele description [Variation Report for NM_024675.4(PALB2):c.13C>T (p.Pro5Ser)]

NM_024675.4(PALB2):c.13C>T (p.Pro5Ser)

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.13C>T (p.Pro5Ser)

Other names:

p.P5S:CCC>TCC

HGVS:

NC_000016.10:g.23641145G>A
NG_007406.1:g.5213C>T
NM_024675.4:c.13C>TMANE SELECT
NP_078951.2:p.Pro5Ser
NP_078951.2:p.Pro5Ser
LRG_308t1:c.13C>T
LRG_308:g.5213C>T
LRG_308p1:p.Pro5Ser
NC_000016.9:g.23652466G>A
NM_024675.3:c.13C>T
p.P5S

Protein change:

P5S

Links:

dbSNP: rs377085677

NCBI 1000 Genomes Browser:

rs377085677

Molecular consequence:

NM_024675.4:c.13C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149977	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 19, 2024)	germline	clinical testing	Citation Link,
SCV000699532	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 23, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24556926, 27616075, 26315354, 27930734, 21285249 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001192899	Leiden Open Variation Database	no assertion criteria provided	Uncertain significance (May 13, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 21285249, 24556926
SCV003917502	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV004222260	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Sep 30, 2022)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21285249, 24556926, 26315354, 27616075, 29052111, 31757951, 28779002, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	unknown	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

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records.

He KY, Zhao Y, McPherson EW, Li Q, Xia F, Weng C, Wang K, He MM.

PLoS One. 2016;11(12):e0167847. doi: 10.1371/journal.pone.0167847.

PubMed [citation]

PMID:: 27930734
PMCID:: PMC5145192

Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.

Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, Stamatoyannopoulos JA, King MC.

Cancer Res. 2011 Mar 15;71(6):2222-9. doi: 10.1158/0008-5472.CAN-10-3958. Epub 2011 Feb 1.

PubMed [citation]

PMID:: 21285249
PMCID:: PMC3059378

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000149977.17

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

Description

Observed in individuals with breast, ovarian, and colorectal cancer (PMID: 21285249, 24556926, 26315354, 28779002, 27616075, 29052111, 28135145, 29522266); Published functional studies demonstrate partially reduced DNA repair efficiency (PMID: 31757951); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21285249, 26315354, 27930734, 28135145, 27616075, 24556926, 29052111, 28779002, 29522266, 20871615, 19369211, Tuncer2023[CaseReport], 31757951)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699532.1

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

Description

Variant summary: The PALB2 c.13C>T (p.Pro5Ser) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 4/118644 control chromosomes at a frequency of 0.0000337, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). This variant has been found in multiple HBOC patients without clear evidence supporting the its pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

#	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 Leiden Open Variation Database, SCV001192899.1

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

Description

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV003917502.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

PALB2: BP1, BP4, BS3:Supporting

#	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		3	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004222260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The frequency of this variant in the general population, 0.000079 (10/126632 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast (PMID: 29052111 (2018), 28779002 (2017), 24556926 (2014), 21285249 (2011)), ovarian (PMID: 27616075 (2016), 26315354 (2015)), or colorectal cancer (PMID: 28135145 (2017)). In a large-scale breast cancer association study, the variant was reported in individuals with breast cancer as well as unaffected study controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). In addition, an experimental study on this variant’s effects on PALB2 protein function yielded inconclusive results (PMID: 31757951 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. 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

Last Updated: Jan 13, 2025

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