NM_024675.4(PALB2):c.1984A>T (p.Lys662Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 2, 2022
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:: RCV001190673.6

Allele description [Variation Report for NM_024675.4(PALB2):c.1984A>T (p.Lys662Ter)]

NM_024675.4(PALB2):c.1984A>T (p.Lys662Ter)

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.1984A>T (p.Lys662Ter)

HGVS:

NC_000016.10:g.23630170T>A
NG_007406.1:g.16188A>T
NM_024675.4:c.1984A>TMANE SELECT
NP_078951.2:p.Lys662Ter
NP_078951.2:p.Lys662Ter
LRG_308t1:c.1984A>T
LRG_308:g.16188A>T
LRG_308p1:p.Lys662Ter
NC_000016.9:g.23641491T>A
NM_024675.3:c.1984A>T

Protein change:

K662*

Links:

dbSNP: rs1555460533

NCBI 1000 Genomes Browser:

rs1555460533

Molecular consequence:

NM_024675.4:c.1984A>T - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001358228	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002719060	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25575445, 30613976 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001358228

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002719060

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 2, 2022)

germline

clinical testing

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

Citation Link

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001358228.2

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

Description

This variant changes 1 nucleotide in exon 5 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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 Ambry Genetics, SCV002719060.2

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

Description

The p.K662* pathogenic mutation (also known as c.1984A>T), located in coding exon 5 of the PALB2 gene, results from an A to T substitution at nucleotide position 1984. This changes the amino acid from a lysine to a stop codon within coding exon 5. This alteration has been reported in individuals with breast cancer, including male breast cancer (Nguyen-Dumont T et al. Breast Cancer Res Treat, 2015 Jan;149:547-54; Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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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