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_024675.4(PALB2):c.109C>A (p.Arg37Ser)

CA191059

185108 (ClinVar)

Gene: PALB2
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 168d5508-5262-4204-bdd9-e319bb7ff161
Approved on: 2023-04-05
Published on: 2023-04-07

HGVS expressions

NM_024675.4:c.109C>A
NM_024675.4(PALB2):c.109C>A (p.Arg37Ser)
NC_000016.10:g.23637952G>T
CM000678.2:g.23637952G>T
NC_000016.9:g.23649273G>T
CM000678.1:g.23649273G>T
NC_000016.8:g.23556774G>T
NG_007406.1:g.8406C>A
ENST00000261584.9:c.109C>A
ENST00000261584.8:c.109C>A
ENST00000561514.1:c.115C>A
ENST00000567003.1:n.387C>A
ENST00000568219.5:c.-777C>A
NM_024675.3:c.109C>A
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Uncertain Significance

Met criteria codes 1
BP1
Not Met criteria codes 4
BS3 BS1 BA1 PM2

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.109C>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by serine at amino acid 37 (p.Arg37Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the African population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in multiple different protein assays (PMID: 31636395); 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. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. 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. (BP1)
Met criteria codes
BP1
PALB2, in which the variant was identified, is defined by the ClinGen HBOP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).
Not Met criteria codes
BS3
This variant is non-functional in multiple different protein assays (31636395); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the ClinGen HBOP VCEP.
Table 1: This variant had a 4.5-fold change in a homology directed DNA repair assay which above 2.4, the authors threshold for benign variation (PMID 31636395). This is ascribed moderate (aka 2 supporting) benign evidence PubMed:31636395
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (2/16254 alleles) in the African population (PM2_Supporting, BS1, and BA1 are not met).
Curation History
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