Variant: NM_024675.3(PALB2):c.3362del (p.Gly1121fs)

CA167019

126739 (ClinVar)

Gene: PALB2

Condition: PALB2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: d8eca774-205b-4826-8339-70e62b4579eb

Approved on: 2023-04-05

Published on: 2025-09-16

HGVS expressions

NM_024675.3:c.3362delG
NM_024675.3(PALB2):c.3362del (p.Gly1121fs)
NC_000016.10:g.23603659del
CM000678.2:g.23603659del
NC_000016.9:g.23614980del
CM000678.1:g.23614980del
NC_000016.8:g.23522481del
NG_007406.1:g.42700del
ENST00000561514.3:c.3368del
ENST00000565038.2:c.*847del
ENST00000566069.6:c.3213del
ENST00000697377.2:c.3206del
ENST00000697379.2:c.3368del
ENST00000561514.2:c.2477del
ENST00000697374.1:c.2477del
ENST00000697375.1:n.4709del
ENST00000697376.1:c.2328del
ENST00000697377.1:c.2315del
ENST00000697378.1:n.3882del
ENST00000697379.1:c.2477del
ENST00000697380.1:n.2566del
ENST00000697381.1:n.2057del
ENST00000697382.1:c.*139del
ENST00000697383.1:c.896del
ENST00000261584.9:c.3362del
ENST00000261584.8:c.3362del
ENST00000566069.5:c.128del
ENST00000568219.5:c.2477del
NM_024675.3:c.3362del
NM_024675.4:c.3362del

Likely Pathogenic

• Met criteria codes: PM5_Supporting PVS1

• Not Met criteria codes: PP1 PM2 BA1 BS4 BS1

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 1.0.0

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.3362del (p.Gly1121fs) variant in PALB2 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay; however, it is a truncation of a functionally important region (removes amino acids 1123-1187) in a gene where 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. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000003979 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified likely 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, PM5_Supporting)

Met criteria codes

• PM5_Supporting: This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the ClinGen HBOP Variant Curation Expert Panel, and is expected to be more deleterious (PM5_Supporting)
• PVS1: The c.3362del (p.Gly1121fs) variant in PALB2 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay; however, it is a truncation of a functionally important region (removes amino acids 1123-1187) in a gene where loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• PP1: This variant has a Bayes factor of 0.751461 based on segregation across 19 families, which falls in the inconclusive range (0.49 to 2.1).
• PM2: This variant has a minor allele frequency in gnomAD v2.1.1 of 0.0003979% in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met).
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: This variant has a Bayes factor of 0.751461 based on segregation across 19 families, which falls in the inconclusive range (0.49 to 2.1).
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline