NM_024675.4(PALB2):c.2087C>T (p.Thr696Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 4, 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:: RCV000132543.14

Allele description [Variation Report for NM_024675.4(PALB2):c.2087C>T (p.Thr696Met)]

NM_024675.4(PALB2):c.2087C>T (p.Thr696Met)

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.2087C>T (p.Thr696Met)

HGVS:

NC_000016.10:g.23630067G>A
NG_007406.1:g.16291C>T
NM_024675.4:c.2087C>TMANE SELECT
NP_078951.2:p.Thr696Met
NP_078951.2:p.Thr696Met
LRG_308t1:c.2087C>T
LRG_308:g.16291C>T
LRG_308p1:p.Thr696Met
NC_000016.9:g.23641388G>A
NM_024675.3:c.2087C>T
p.T696M

Protein change:

T696M

Links:

dbSNP: rs587780820

NCBI 1000 Genomes Browser:

rs587780820

Molecular consequence:

NM_024675.4:c.2087C>T - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187640	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 3, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25575445, 28779002, 31214711, 32832836, 33113089 Citation Link,
SCV000903299	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 4, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 25575445, 28779002, 30287823, 31214711, 32980694, 33113089, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187640

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 3, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000903299

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 4, 2023)

germline

clinical testing

PubMed (8)
[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

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

Matejcic M, Patel Y, Lilyquist J, Hu C, Lee KY, Gnanaolivu RD, Hart SN, Polley EC, Yadav S, Boddicker NJ, Samara R, Xia L, Sheng X, Lubmawa A, Kiddu V, Masaba B, Namuguzi D, Mutema G, Job K, Henry DM, Ingles SA, Wilkens L, et al.

JCO Precis Oncol. 2020;4:32-43. doi: 10.1200/po.19.00179. Epub 2020 Jan 31.

PubMed [citation]

PMID:: 32832836
PMCID:: PMC7442213

Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry.

Nguyen-Dumont T, Hammet F, Mahmoodi M, Tsimiklis H, Teo ZL, Li R, Pope BJ, Terry MB, Buys SS, Daly M, Hopper JL, Winship I, Goldgar DE, Park DJ, Southey MC.

Breast Cancer Res Treat. 2015 Jan;149(2):547-54. doi: 10.1007/s10549-014-3260-8. Epub 2015 Jan 10.

PubMed [citation]

PMID:: 25575445
PMCID:: PMC4542063

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000187640.9

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

Description

The p.T696M variant (also known as c.2087C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2087. The threonine at codon 696 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in individuals with a personal or family history of breast cancer (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590) This variant was present in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43) but was only seen in one individual from the control group in a Japanese study of prostate cancer patients (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, SCV000903299.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces threonine with methionine at codon 696 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual and a family affected with breast cancer (PMID: 25575445, 33113089) and in breast cancer case-control studies in 1/13824 cases and 0/5488 unaffected individuals (PMID: 28779002) and in 2/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010449). This variant also has been reported in male breast cancer, pancreatic cancer and prostate cancer case-control studies, in which the variant is only detected in unaffected individuals and not found in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 4/251484 chromosomes 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: Nov 3, 2024

ClinVar

Relating variation to medicine