Variant: NM_024675.3(PALB2):c.1592del (p.Leu531fs)

CA250432

126609 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 725ba8c8-354c-473f-9133-b2c40facf7ec

Approved on: 2023-04-05

Published on: 2023-04-07

HGVS expressions

NM_024675.3:c.1592del
NM_024675.3:c.1592delT
NM_024675.3(PALB2):c.1592del (p.Leu531fs)
NC_000016.10:g.23634957del
CM000678.2:g.23634957del
NC_000016.9:g.23646278del
CM000678.1:g.23646278del
NC_000016.8:g.23553779del
NG_007406.1:g.11404del
ENST00000261584.9:c.1592del
ENST00000261584.8:c.1592del
ENST00000565038.1:n.86+2896del
ENST00000568219.5:c.707del
NM_024675.4:c.1592del
NM_024675.4(PALB2):c.1592del (p.Leu531fs)

Pathogenic

• Met criteria codes: PM5_Supporting PVS1 PP1_Strong PS4

• Not Met criteria codes: BS1 PS3 PM2

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.1592del (p.L531Cfs*30) variant in PALB2 is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [HR 6.1 (95% CI 2.2-17.2, p = 0.01)] (PMID: 18628482). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. The variant has been reported to segregate with breast cancer in 6 affected family members from three families (Ambry Genetics and Invitae). The minor allele frequency in gnomAD v2.1.1 is 0.001871 in the Finnish population; however, this variant known to be a Finnish founder mutation thus explaining the higher than expected population frequency (PM2_Supporting, BS1, and BA1 are not met; PMID: 17287723). In summary, this variant meets criteria to be classified as 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, PS4, PP1_Strong, 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 HBOP VCEP, and is expected to be more deleterious.
• PVS1: The c.1592delT (p.L531Cfs*30) variant in PALB2 is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon 4/13 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 31757951).
• PP1_Strong: COOL segregation analysis from 3 families (Ambry and Invitae internal data) Co-segregation overall LOD score: 1.6056 Co-segregation overall Bayes factor: 40.32737929761131281396 Co-segregation in each pedigree (empty if there is only one pedigree): Ped1=0.550991 Ped2=0.587469 Ped3=0.467144
• PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [HR 6.1 (95% CI 2.2-17.2, p = 0.01)] (PMID: 18628482).

Not Met criteria codes

• BS1: Finnish minor allele frequency in gnomAD v2.1.1 is 0.187% (47/25120 alleles) in the Finnish population, which is higher than the HBOP VCEP threshold (>0.01%) for BS1; however, this is a known founder variant thus explaining the high population frequency.
• PS3: This variant is non-functional in protein assays (PMID: 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.
• PM2: Finnish minor allele frequency in gnomAD v2.1.1 is 0.187% (47/25120 alleles) in the Finnish population, which is higher than the HBOP VCEP threshold (>0.01%) for BS1; however, this is a known founder variant thus explaining the high population frequency.