Variant: NM_024675.4(PALB2):c.104T>C (p.Leu35Pro)

CA279502031

657328 (ClinVar)

Gene: PALB2

Condition: PALB2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 0f82663c-1189-4b63-a562-863711d62915

Approved on: 2022-09-15

Published on: 2025-09-16

HGVS expressions

NM_024675.4:c.104T>C
NM_024675.4(PALB2):c.104T>C (p.Leu35Pro)
NC_000016.10:g.23638074A>G
CM000678.2:g.23638074A>G
NC_000016.9:g.23649395A>G
CM000678.1:g.23649395A>G
NC_000016.8:g.23556896A>G
NG_007406.1:g.8284T>C
ENST00000561514.3:c.110T>C
ENST00000565038.2:c.104T>C
ENST00000566069.6:c.104T>C
ENST00000697377.2:c.110T>C
ENST00000697379.2:c.110T>C
ENST00000561514.2:c.-782T>C
ENST00000697374.1:c.-782T>C
ENST00000697375.1:n.1451T>C
ENST00000697376.1:c.-818T>C
ENST00000697377.1:c.-782T>C
ENST00000697378.1:n.624T>C
ENST00000697379.1:c.-782T>C
ENST00000697382.1:c.-782T>C
ENST00000697383.1:c.48+3036T>C
ENST00000697384.1:n.258T>C
ENST00000261584.9:c.104T>C
ENST00000261584.8:c.104T>C
ENST00000561514.1:c.110T>C
ENST00000567003.1:n.382T>C
ENST00000568219.5:c.-782T>C
NM_024675.3:c.104T>C

Uncertain Significance

• Met criteria codes: PP1 BP1 PM2_Supporting

• Not Met criteria codes: PS3 PP3

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 1.1.0

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.104T>C variant in PALB2 is a missense variant predicted to cause substitution of leucine by proline at amino acid 35 (p.Leu35Pro). This variant is absent in gnomAD v2.1.1. The variant has been reported to segregate with breast cancer in 3 affected family members from one family (PMID: 28319063). This variant is non-functional in multiple protein assays (PMID: 31586400; 31636395; 31757951); however, due to a lack of positive missense controls with known clinical impact, these 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 a autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM2_Supporting, PP1, BP1)

Met criteria codes

• PP1: The variant has been reported to segregate with breast cancer in 3 affected family members from one family (PP1; PMID: 28319063).
• BP1: PALB2, in which the variant was identified, is defined by the ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008476 in European (non-Finnish) population, which is lower than the ClinGen HBOP VCEP threshold (<0.0000033) for PM2_Supporting, meeting this criterion.

Not Met criteria codes

• PS3: This variant is non-functional in multiple protein assays (31586400; 31636395; 31757951); however due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the ClinGen HBOP VCEP.
• PP3: Not applicable as multiple predictors have failed to predict the functional outcome for PALB2 missense variants.