Submissions for variant NM_024675.4(PALB2):c.3232T>A (p.Cys1078Ser)

gnomAD frequency: 0.00001  dbSNP: rs876659587

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214649	SCV000276206	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-05	criteria provided, single submitter	clinical testing	The p.C1078S variant (also known as c.3232T>A), located in coding exon 12 of the PALB2 gene, results from a T to A substitution at nucleotide position 3232. The cysteine at codon 1078 is replaced by serine, an amino acid with dissimilar properties. This alteration was detected in 1/1231 colorectal cancer cases and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This alteration was also detected in a cohort of 690 patients with myeloid malignancy (Li ST et al. Leukemia, 2020 06;34:1675-1678). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530258	SCV000633413	uncertain significance	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1078 of the PALB2 protein (p.Cys1078Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232150). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000214649	SCV001734494	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 1078 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This protein change has been reported in individuals affected with breast cancer (PMID: 28779002, 30638972). This variant has been identified in 1/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001788088	SCV002030933	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in individuals with colorectal cancer or myeloid malignancy (DeRycke et al., 2017; Li et al., 2020); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 30638972, 31911633, 28944238, 28779002)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230458	SCV003928583	uncertain significance	not specified	2023-04-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000530258	SCV005053890	uncertain significance	Familial cancer of breast	2024-02-14	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030400	SCV001193373	uncertain significance	Carcinoma of colon	2017-01-31	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Melissa DeRycke.