NM_024675.4(PALB2):c.3278T>C (p.Ile1093Thr) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 28, 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:: RCV000160854.5

Allele description [Variation Report for NM_024675.4(PALB2):c.3278T>C (p.Ile1093Thr)]

NM_024675.4(PALB2):c.3278T>C (p.Ile1093Thr)

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.3278T>C (p.Ile1093Thr)

Other names:

p.I1093T:ATT>ACT

HGVS:

NC_000016.10:g.23607936A>G
NG_007406.1:g.38422T>C
NM_024675.4:c.3278T>CMANE SELECT
NP_078951.2:p.Ile1093Thr
NP_078951.2:p.Ile1093Thr
LRG_308t1:c.3278T>C
LRG_308:g.38422T>C
LRG_308p1:p.Ile1093Thr
NC_000016.9:g.23619257A>G
NM_024675.3:c.3278T>C

Protein change:

I1093T

Links:

dbSNP: rs45616636

NCBI 1000 Genomes Browser:

rs45616636

Molecular consequence:

NM_024675.4:c.3278T>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
SCV000211533	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 25, 2020)	germline	clinical testing	Citation Link,
SCV002046125	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 28, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25575445, 28873162, 31636395, 31586400, 34326862, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211533

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 25, 2020)

germline

clinical testing

Citation Link,

SCV002046125

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 28, 2023)

unknown

clinical testing

PubMed (6)
[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

Nothing to display

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000211533.12

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

Description

Published functional studies demonstrate no damaging effect: homology-directed repair, BRCA2 interaction, and nuclear localization similar to wildtype (Rodrigue 2019, Wiltshire 2019); Observed in individuals with personal or family history of breast cancer (Nguyen-Dumont 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31586400, 25575445, 28873162, 31636395)

#	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, SCV002046125.2

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

Description

In the published literature, this variant has been reported in individuals with unspecified cancers (PMIDs: 28873162 (2017) and 34326862 (2021)), as well as breast cancer (PMID: 25575445 (2015)). In addition, functional studies have shown that this variant results in normal HDR activity, PARP inhibitor olaparib sensitivity, and BRCA2 binding (PMIDs: 31586400 (2019) and 31636395 (2020)). The frequency of this variant in the general population, 0.000008 (2/251486 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: Nov 18, 2024

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