ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 734 of the PALB2 protein (p.Thr734Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and/or ovarian cancer or clinical features of Lynch syndrome (PMID: 25980754, 35610400). ClinVar contains an entry for this variant (Variation ID: 241541). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. 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.

This missense variant replaces threonine with asparagine at codon 734 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 variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010925) and in one individual each suspected of having Lynch syndrome (PMID: 25980754) and affected with breast cancer (PMID: 32885271) and unspecified cancer (PMID: 28873162). This variant has been identified in 3/251490 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.

The p.T734N variant (also known as c.2201C>A), located in coding exon 5 of the PALB2 gene, results from a C to A substitution at nucleotide position 2201. The threonine at codon 734 is replaced by asparagine, an amino acid with similar properties. This alteration was identified in a cohort of 1040 patients with advanced cancer; however, specific clinical information on this individual was not provided (Mandelker D et al. JAMA, 2017 09;318:825-835). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly 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.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

PALB2: BP1, BP4

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; Observed in individuals with personal or family history of breast or ovarian cancer and in an individual who had a history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 32885271, 35610400, 38061684); This variant is associated with the following publications: (PMID: 28873162, 28069802, 25980754, 22941656, 32885271, 35610400, 38061684)

Variant summary: PALB2 c.2201C>A (p.Thr734Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251490 control chromosomes, predominantly at a frequency of 5.8e-05 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2201C>A has been reported in the literature in one unspecified individual affected with Breast Cancer (Gonzalez_2022). A large case-control study evaluating breast cancer genetic risk also reported this variant was present in both the case and the control cohorts (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35610400, 33471991). ClinVar contains an entry for this variant (Variation ID: 241541). Based on the evidence outlined above, the variant was classified as uncertain significance.

The PALB2 c.2201C>A variant is predicted to result in the amino acid substitution p.Thr734Asn. This variant has been reported in individuals with breast and/or ovarian cancer and in an individual with suspected Lynch syndrome (see, for example, Supplementary Material S1, Gonzalez et al. 2022. PubMed ID: 35610400; Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Supplementary data, Dorling et al. 2021. PubMed ID: 33471991). It has also been observed in controls (Supplementary data, Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. It is interpreted as uncertain or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/241541/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.