Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_024675.3(PALB2):c.2559C>T (p.Gly853=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA269540

126660 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f11ca490-40a5-4cbc-bd48-5e9869d438f1

Approved on: 2023-04-05

Published on: 2023-04-07

HGVS expressions

NM_024675.3:c.2559C>T

NM_024675.3(PALB2):c.2559C>T (p.Gly853=)

NC_000016.10:g.23629231G>A

CM000678.2:g.23629231G>A

NC_000016.9:g.23640552G>A

CM000678.1:g.23640552G>A

NC_000016.8:g.23548053G>A

NG_007406.1:g.17127C>T

ENST00000261584.9:c.2559C>T

ENST00000261584.8:c.2559C>T

ENST00000565038.1:n.131C>T

ENST00000568219.5:c.1674C>T

NM_024675.4:c.2559C>T

NM_024675.4(PALB2):c.2559C>T (p.Gly853=)

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM5_Supporting

PP3 PM2 PS3

Evidence Links 0

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.2559C>T (p.Gly853=) variant is a synonymous (silent) variant in PALB2. This variant has a minor allele frequency in gnomAD of 0.00001758 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This alteration is observed to introduce a cryptic splice site causing a 29 base pair deletion in exon 6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 31843900, 32133419). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM5_supporting criteria)

PVS1

The c.2559C>T (p.Gly853=) variant in PALB2 is observed to introduce a cryptic splice site causing a 29 base pair deletion in exon 6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 31843900, 32133419).

PM5_Supporting

This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious (PM5_Supporting).

PP3

Splice AI and varSEAK predict splice defect; cannot be applied in addition to PVS1

PM2

Present in 2 alleles in NFE population

PS3

See RNA studies discussed as PVS1 evidence

Curation History

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