NM_024675.4(PALB2):c.1273G>A (p.Val425Met) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 16, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000236471.21

Allele description [Variation Report for NM_024675.4(PALB2):c.1273G>A (p.Val425Met)]

NM_024675.4(PALB2):c.1273G>A (p.Val425Met)

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.1273G>A (p.Val425Met)

HGVS:

NC_000016.10:g.23635273C>T
NG_007406.1:g.11085G>A
NM_024675.4:c.1273G>AMANE SELECT
NP_078951.2:p.Val425Met
NP_078951.2:p.Val425Met
LRG_308t1:c.1273G>A
LRG_308:g.11085G>A
LRG_308p1:p.Val425Met
NC_000016.9:g.23646594C>T
NM_024675.3:c.1273G>A
Q86YC2:p.Val425Met
p.V425M

Protein change:

V425M

Links:

UniProtKB: Q86YC2#VAR_066366; dbSNP: rs576081828

NCBI 1000 Genomes Browser:

rs576081828

Molecular consequence:

NM_024675.4:c.1273G>A - 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
SCV000292646	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jan 15, 2021)	germline	clinical testing	Citation Link,
SCV001134534	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 16, 2023)	unknown	clinical testing	PubMed (17) [See all records that cite these PMIDs] 32041954, 28135145, 32561490, 35610400, 33309985, 32885271, 31214711, 36243179, 30287823, 21618343, 26489409, 28825143, 25980754, 18446436, 20722467, 29387807, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000292646

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Jan 15, 2021)

germline

clinical testing

Citation Link,

SCV001134534

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 16, 2023)

unknown

clinical testing

PubMed (17)
[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

PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1.

Belotserkovskaya R, Raga Gil E, Lawrence N, Butler R, Clifford G, Wilson MD, Jackson SP.

Nat Commun. 2020 Feb 10;11(1):819. doi: 10.1038/s41467-020-14563-y.

PubMed [citation]

PMID:: 32041954
PMCID:: PMC7010753

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]

PMID:: 28135145
PMCID:: PMC5455355

See all PubMed Citations (17)

Details of each submission

From GeneDx, SCV000292646.12

#	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 associated with the following publications: (PMID: 20722467, 28825143, 18446436, 21618343, 25980754, 29387807, 26489409)

#	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, SCV001134534.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 18446436 (2009), 20722467 (2010), 21618343 (2011), 26489409 (2015), 28825143 (2017), 30287823 (2018)), a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754 (2015)), colorectal cancer (PMIDs: 28135145 (2017), 33309985 (2020)), prostate cancer (PMID: 31214711 (2020)), as well as in unaffected individuals (PMIDs: 20722467 (2010), 30287823 (2018), 33309985 (2020)). One functional study reported that this variant does not interfere with histone binding as a part of DNA repair (PMID: 32041954 (2020)), however further research is needed. The frequency of this variant in the general population, 0.0015 (21/14420 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 benign. 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: Oct 26, 2024

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