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]
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Variant: NM_024675.3(PALB2):c.1684+1G>A

CA395129867

482029 (ClinVar)

Gene: PALB2
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: cd7eff7f-6a51-419b-99ed-c2ddb418f78a

HGVS expressions

NM_024675.3:c.1684+1G>A
NM_024675.3(PALB2):c.1684+1G>A
NC_000016.10:g.23634861C>T
CM000678.2:g.23634861C>T
NC_000016.9:g.23646182C>T
CM000678.1:g.23646182C>T
NC_000016.8:g.23553683C>T
NG_007406.1:g.11497G>A
ENST00000561514.3:c.1690+1G>A
ENST00000565038.2:c.211+2989G>A
ENST00000566069.6:c.1684+1G>A
ENST00000697377.2:c.1690+1G>A
ENST00000697379.2:c.1690+1G>A
ENST00000561514.2:c.799+1G>A
ENST00000697374.1:c.799+1G>A
ENST00000697375.1:n.3031+1G>A
ENST00000697376.1:c.799+1G>A
ENST00000697377.1:c.799+1G>A
ENST00000697378.1:n.2204+1G>A
ENST00000697379.1:c.799+1G>A
ENST00000697382.1:c.799+1G>A
ENST00000697383.1:c.49-5586G>A
ENST00000697384.1:n.1838+1G>A
ENST00000261584.9:c.1684+1G>A
ENST00000261584.8:c.1684+1G>A
ENST00000565038.1:c.86+2989G>A
ENST00000568219.5:c.799+1G>A
NM_024675.4:c.1684+1G>A
NM_024675.4(PALB2):c.1684+1G>A

Uncertain Significance

Met criteria codes 2
PM2_Supporting PVS1_Strong
Not Met criteria codes 2
PP1 PM5

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.1684+1G>A variant in PALB2 occurs within the canonical splice donor (+1,2) of intron 4. Minigene analysis demonstrated that the variant impacts splicing by causing multicassette skipping of exons 4 and 5 which is predicted to result in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 30890586). This variant is absent from gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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_Strong(RNA), PM2_Supporting)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PVS1_Strong
The c.1684+1G>A variant in PALB2 occurs within the canonical splice donor (+1,2) of intron 4. Minigene analysis demonstrated that the variant impacts splicing by causing multicassette skipping of exons 4 and 5 which is predicted to result in an in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong(RNA); PMID 30890586)
Not Met criteria codes
PP1
Based on one pedigree: Bayes factor .9432891
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2024-01-05
Published on: 2024-02-14
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