NM_024675.4(PALB2):c.2752C>T (p.Pro918Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000165106.15

Allele description [Variation Report for NM_024675.4(PALB2):c.2752C>T (p.Pro918Ser)]

NM_024675.4(PALB2):c.2752C>T (p.Pro918Ser)

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.2752C>T (p.Pro918Ser)

HGVS:

NC_000016.10:g.23624091G>A
NG_007406.1:g.22267C>T
NM_024675.4:c.2752C>TMANE SELECT
NP_078951.2:p.Pro918Ser
NP_078951.2:p.Pro918Ser
LRG_308t1:c.2752C>T
LRG_308:g.22267C>T
LRG_308p1:p.Pro918Ser
NC_000016.9:g.23635412G>A
NM_024675.3:c.2752C>T
p.P918S
p.Pro918Ser

Protein change:

P918S

Links:

dbSNP: rs515726094

NCBI 1000 Genomes Browser:

rs515726094

Molecular consequence:

NM_024675.4:c.2752C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215816	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21285249, 28779002, 29522266, 30883245 Citation Link,
SCV000685974	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21285249, 28779002, 29522266, 31843900, 33471991, 25741868
SCV000886698	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Jul 13, 2018)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215816

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 29, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000685974

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 8, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000886698

True Health Diagnostics

no assertion criteria provided

Uncertain significance
(Jul 13, 2018)

germline

clinical testing

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

Citations

PubMed

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance.

Abe T, Blackford AL, Tamura K, Ford M, McCormick P, Chuidian M, Almario JA, Borges M, Lennon AM, Shin EJ, Klein AP, Hruban RH, Canto MI, Goggins M.

J Clin Oncol. 2019 May 1;37(13):1070-1080. doi: 10.1200/JCO.18.01512. Epub 2019 Mar 18.

PubMed [citation]

PMID:: 30883245
PMCID:: PMC6494358

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 (7)

Details of each submission

From Ambry Genetics, SCV000215816.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.P918S variant (also known as c.2752C>T), located in coding exon 8 of the PALB2 gene, results from a C to T substitution at nucleotide position 2752. The proline at codon 918 is replaced by serine, an amino acid with similar properties. This alteration was reported in 4/1144 BRCA1/2 negative breast cancer patients with at least two relatives diagnosed with breast cancer (Casadei S et al. Cancer Res., 2011 Mar;71:2222-9). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). Additionally, this alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also detected in a high-risk individual undergoing pancreatic cancer screening (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000685974.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces proline with serine at codon 918 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. An RNA study has reported that this variant does not impact mRNA splicing (PMID: 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast cancer (PMID: 21285249, 28779002, 29522266) and has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010192). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 True Health Diagnostics, SCV000886698.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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