NM_024675.4(PALB2):c.3539T>C (p.Ile1180Thr) AND not provided

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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 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:: RCV000479423.4

Allele description

NM_024675.4(PALB2):c.3539T>C (p.Ile1180Thr)

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.3539T>C (p.Ile1180Thr)

HGVS:

NC_000016.10:g.23603481A>G
NG_007406.1:g.42877T>C
NM_024675.4:c.3539T>CMANE SELECT
NP_078951.2:p.Ile1180Thr
NP_078951.2:p.Ile1180Thr
LRG_308t1:c.3539T>C
LRG_308:g.42877T>C
LRG_308p1:p.Ile1180Thr
NC_000016.9:g.23614802A>G
NM_024675.3:c.3539T>C

Protein change:

I1180T

Links:

dbSNP: rs180177139

NCBI 1000 Genomes Browser:

rs180177139

Molecular consequence:

NM_024675.4:c.3539T>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
SCV000568195	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jul 31, 2018)	germline	clinical testing	Citation Link,
SCV004222347	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 8, 2023)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 30613976, 28825729, 20180015, 31586400, 31636395, 31757951, 30638972, 32830346, 33195396, 33606809, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568195

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jul 31, 2018)

germline

clinical testing

Citation Link,

SCV004222347

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 8, 2023)

unknown

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

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

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.

Rizzolo P, Zelli V, Silvestri V, Valentini V, Zanna I, Bianchi S, Masala G, Spinelli AM, Tibiletti MG, Russo A, Varesco L, Giannini G, Capalbo C, Calistri D, Cortesi L, Viel A, Bonanni B, Azzollini J, Manoukian S, Montagna M, Peterlongo P, Radice P, et al.

Int J Cancer. 2019 Jul 15;145(2):390-400. doi: 10.1002/ijc.32106. Epub 2019 Jan 24. Erratum in: Int J Cancer. 2020 Jul 15;147(2):E2. doi: 10.1002/ijc.32944.

PubMed [citation]

PMID:: 30613976

A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.

Gadd S, Huff V, Walz AL, Ooms AHAG, Armstrong AE, Gerhard DS, Smith MA, Auvil JMG, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Hermida LC, Davidsen T, Gesuwan P, Ma Y, Zong Z, Mungall AJ, Moore RA, Marra MA, et al.

Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21.

PubMed [citation]

PMID:: 28825729
PMCID:: PMC5712232

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000568195.4

#	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 denoted PALB2 c.3539T>C at the cDNA level, p.Ile1180Thr (I1180T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant was observed in a male with breast cancer (Silvestri 2010). PALB2 Ile1180Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the WD7 repeat, the region of interaction with RAD51, BRCA2 and POLH, and the region required for stimulation of POLH DNA synthesis (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PALB2 Ile1180Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	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, SCV004222347.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

In the published literature, this variant has been reported in individuals with breast cancer, male breast cancer, and kidney cancer (PMIDs: 20180015 (2010), 30613976 (2019), 33606809 (2021), and 32830346 (2021)). Studies have shown that this variant has no significant effect on PALB2 function using an HDR assay or PARP inhibitor sensitivity assay (PMIDs: 31757951 (2019), 31586400 (2019), and 31636395 (2020)). The frequency of this variant in the general population, 0.000004 (1/251458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 predictions that this variant is 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

Last Updated: Sep 8, 2024

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