NM_024675.4(PALB2):c.3125C>G (p.Thr1042Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 23, 2018
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:: RCV000589774.2

Allele description [Variation Report for NM_024675.4(PALB2):c.3125C>G (p.Thr1042Ser)]

NM_024675.4(PALB2):c.3125C>G (p.Thr1042Ser)

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.3125C>G (p.Thr1042Ser)

Other names:

p.T1042S:ACT>AGT

HGVS:

NC_000016.10:g.23614080G>C
NG_007406.1:g.32278C>G
NM_024675.4:c.3125C>GMANE SELECT
NP_078951.2:p.Thr1042Ser
NP_078951.2:p.Thr1042Ser
LRG_308t1:c.3125C>G
LRG_308:g.32278C>G
LRG_308p1:p.Thr1042Ser
NC_000016.9:g.23625401G>C
NM_024675.3:c.3125C>G

Protein change:

T1042S

Links:

dbSNP: rs587780215

NCBI 1000 Genomes Browser:

rs587780215

Molecular consequence:

NM_024675.4:c.3125C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Hadaka virus 1 7n genomic RNA, segment 10, complete sequence
Hadaka virus 1 7n genomic RNA, segment 10, complete sequence
gi|2500668976|ref|NC_078569.1|

Nucleotide
asparaginase ASP3-4 [Saccharomyces cerevisiae S288C]
asparaginase ASP3-4 [Saccharomyces cerevisiae S288C]
gi|6323189|ref|NP_013261.1|

Protein
Pyrus pyrifolia
Pyrus pyrifolia
RNA-seq data of pear fruits

BioProject
Pericrocotus ethologus
Pericrocotus ethologus
Pericrocotus ethologus RefSeq Genome

BioProject
CCDC12 coiled-coil domain containing 12 [Sus scrofa]
CCDC12 coiled-coil domain containing 12 [Sus scrofa]
Gene ID:100515924

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000150006	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Feb 23, 2018)	germline	clinical testing	Citation Link,
SCV000699584	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 21, 2017)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000150006

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Feb 23, 2018)

germline

clinical testing

Citation Link,

SCV000699584

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 21, 2017)

germline

clinical testing

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000150006.11

#	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 denoted PALB2 c.3125C>G at the cDNA level, p.Thr1042Ser (T1042S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Thr1042Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the WD4 repeat region and the region of interaction with BRCA2, RAD51, and POLH that is required for 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 Thr1042Ser 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699584.1

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

Description

Variant summary: The PALB2 c.3125C>G (p.Thr1042Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant . This variant was found in 1/109874 control chromosomes at a frequency of 0.0000091, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). In addition, one clinical diagnostic laboratory has classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

#	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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