NM_024675.4(PALB2):c.3035C>T (p.Thr1012Ile) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 16, 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:: RCV000479556.5

Allele description [Variation Report for NM_024675.4(PALB2):c.3035C>T (p.Thr1012Ile)]

NM_024675.4(PALB2):c.3035C>T (p.Thr1012Ile)

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.3035C>T (p.Thr1012Ile)

HGVS:

NC_000016.10:g.23621440G>A
NG_007406.1:g.24918C>T
NM_024675.4:c.3035C>TMANE SELECT
NP_078951.2:p.Thr1012Ile
NP_078951.2:p.Thr1012Ile
LRG_308t1:c.3035C>T
LRG_308:g.24918C>T
LRG_308p1:p.Thr1012Ile
NC_000016.9:g.23632761G>A
NM_024675.3:c.3035C>T

Protein change:

T1012I

Links:

dbSNP: rs761032954

NCBI 1000 Genomes Browser:

rs761032954

Molecular consequence:

NM_024675.4:c.3035C>T - 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
SCV000569463	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 10, 2020)	germline	clinical testing	Citation Link,
SCV004222333	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 16, 2023)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 33471991, 28825143, 26489409, 25980754, 35610400, 33811135, 35853885, 30638972, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000569463

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Mar 10, 2020)

germline

clinical testing

Citation Link,

SCV004222333

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 16, 2023)

unknown

clinical testing

PubMed (9)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer.

Zhang K, Zhou J, Zhu X, Luo M, Xu C, Yu J, Deng M, Zheng S, Chen Y.

Breast Cancer Res Treat. 2017 Dec;166(3):865-873. doi: 10.1007/s10549-017-4425-z. Epub 2017 Aug 20.

PubMed [citation]

PMID:: 28825143

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000569463.5

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and other cancers (Li 2015, Yurgelun 2015, Zhang 2017); This variant is associated with the following publications: (PMID: 26489409, 25980754, 28825143, 26692951)

#	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, SCV004222333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 26489409 (2015), 28825143 (2017), 33811135 (2022)) and an undescribed Lynch syndrome associated cancer or polyps (PMID: 25980754 (2015)). This variant has also been reported in affected and control individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). One functional study observed the variant to have only a modest reduction in homologous recombination DNA repair (PMID: 35853885 (2022)) and further research is needed. The frequency of this variant in the general population, 0.00076 (11/14424 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 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

Last Updated: Sep 29, 2024

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