NM_024675.4(PALB2):c.371C>A (p.Thr124Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 6, 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:: RCV000573383.9

Allele description [Variation Report for NM_024675.4(PALB2):c.371C>A (p.Thr124Asn)]

NM_024675.4(PALB2):c.371C>A (p.Thr124Asn)

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.371C>A (p.Thr124Asn)

HGVS:

NC_000016.10:g.23636175G>T
NG_007406.1:g.10183C>A
NM_024675.4:c.371C>AMANE SELECT
NP_078951.2:p.Thr124Asn
NP_078951.2:p.Thr124Asn
LRG_308t1:c.371C>A
LRG_308:g.10183C>A
LRG_308p1:p.Thr124Asn
NC_000016.9:g.23647496G>T
NM_024675.3:c.371C>A

Protein change:

T124N

Links:

dbSNP: rs45457297

NCBI 1000 Genomes Browser:

rs45457297

Molecular consequence:

NM_024675.4:c.371C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Family with sequence simliarity 151, member A [Mus musculus]
Family with sequence simliarity 151, member A [Mus musculus]
gi|19354457|gb|AAH24430.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000670724	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30287823, 31214711 Citation Link,
SCV001357583	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30287823, 31214711, 32980694, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000670724

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 6, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001357583

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2022)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls.

Momozawa Y, Iwasaki Y, Hirata M, Liu X, Kamatani Y, Takahashi A, Sugano K, Yoshida T, Murakami Y, Matsuda K, Nakagawa H, Spurdle AB, Kubo M.

J Natl Cancer Inst. 2020 Apr 1;112(4):369-376. doi: 10.1093/jnci/djz124.

PubMed [citation]

PMID:: 31214711
PMCID:: PMC7156928

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000670724.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.T124N variant (also known as c.371C>A), located in coding exon 4 of the PALB2 gene, results from a C to A substitution at nucleotide position 371. The threonine at codon 124 is replaced by asparagine, an amino acid with similar properties. This alteration was observed in unselected female breast cancer patients, unselected prostate cancer patients and unaffected controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV001357583.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces threonine with asparagine at codon 124 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two breast cancer case-control studies in which it was detected in 2 cases and 2 unaffected individuals (PMID: 30287823, 33471991). This variant also has been reported in a pancreatic cancer and a prostate cancer case-control study in 1/1005 pancreatic cancer cases and 4/23705 unaffected controls and 3/7636 prostate cancer cases and 2/12366 unaffected controls, respectively (PMID: 31214711, 32980694). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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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