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.3113G>A (p.Trp1038Ter)

CA251004

126711 (ClinVar)

Gene: PALB2
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: 213dcc73-14c2-426c-a6e0-46d72f288c00
Approved on: 2023-04-05
Published on: 2023-04-07

HGVS expressions

NM_024675.3:c.3113G>A
NM_024675.3(PALB2):c.3113G>A (p.Trp1038Ter)
NC_000016.10:g.23621362C>T
CM000678.2:g.23621362C>T
NC_000016.9:g.23632683C>T
CM000678.1:g.23632683C>T
NC_000016.8:g.23540184C>T
NG_007406.1:g.24996G>A
ENST00000261584.9:c.3113G>A
ENST00000261584.8:c.3113G>A
ENST00000566069.5:n.28G>A
ENST00000568219.5:c.2228G>A
NM_024675.4:c.3113G>A
NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)
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Pathogenic

Met criteria codes 3
PS4 PVS1 PM5_Supporting
Not Met criteria codes 4
PS3 PP3 PM2 BS1

Evidence Links 1

Expert Panel

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.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID: 21285249, 23448497). 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. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID: 27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as 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), PS4, PM5_Supporting).
Met criteria codes
PS4
Case Control Study with OR ≥3, p≤.05 (PMID: 27595995)
PVS1
The c.3113G>A (p.Trp1038Ter) variant causes a splice defect that disrupts a critical functional domain, as demonstrated by high quality RNA studies supporting PVS1 (PMIDs: 21285249, 23448497).
PM5_Supporting
Premature termination upstream of p.Tyr1183 which is expected to be more severe than the most C-terminal pathogenic variant p.Tyr1183* (Reid 2007 PMID 17200671, Oliver 2009 PMID 19609323, Boonen 2020 PMID 33195396)
Not Met criteria codes
PS3
This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP.

PP3
In silico predictors (MaxENT/SpliceAI) are in agreement this variant affects splicing. However PVS1 applied therefore n/a.
PM2
BS1
gnomAD filtering allele frequency is 0.006665% in the European (Non-Finnish) is not greater than the PALB2 BS1 threshold of 0.01%
Curation History
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