Evidence Repository
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.2074C>T (p.Gln692Ter)

CA294556

143966 (ClinVar)

Gene: PALB2
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b1afce5b-5094-4d86-9eea-9cd72732a7f7
Approved on: 2023-04-05
Published on: 2023-04-07

HGVS expressions

NM_024675.3:c.2074C>T
NM_024675.3(PALB2):c.2074C>T (p.Gln692Ter)
NC_000016.10:g.23630080G>A
CM000678.2:g.23630080G>A
NC_000016.9:g.23641401G>A
CM000678.1:g.23641401G>A
NC_000016.8:g.23548902G>A
NG_007406.1:g.16278C>T
ENST00000261584.9:c.2074C>T
ENST00000261584.8:c.2074C>T
ENST00000565038.1:n.87-805C>T
ENST00000568219.5:c.1189C>T
NM_024675.4:c.2074C>T
NM_024675.4(PALB2):c.2074C>T (p.Gln692Ter)
More

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 2
PM5_Supporting PVS1
Not Met criteria codes 2
PP1 PM2

Evidence Links 0

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.2074C>T (p.Gln692Ter) variant in PALB2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting)
Met criteria codes
PM5_Supporting
This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183Ter), as classified by the ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer VCEP, and is expected to be more deleterious (PM5_Supporting).
PVS1
The c.2074C>T (p.Gln692Ter) variant in PALB2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
Not Met criteria codes
PP1
This variant has a Bayes factor of 0.9862 based on segregation in one family.
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113760 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met).
Curation History
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