ClinVar Genomic variation as it relates to human health

Variant summary: PALB2 c.2228A>G (p.Tyr743Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 313070 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Notably, the variant was detected at a frequency of 0.0170 in a large study of Japanese controls (Momozawa_2018), providing further supporting evidence for a benign role. c.2228A>G has been reported in the literature in individuals at risk or affected by Hereditary Breast and Ovarian Cancer or pancreatic ductal adenocarcinoma (Momozawa_2018, Ohmoto_2018, Takeuchi_2018, Sato_2017, Balmana_2016, Nakagomi_2015, Ramus_2015, Thompson, 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a likely pathogenic variant has been reported in our internal database (MSH2 c.1511-1G>A). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 29802286, 26315354, 26283626, 29338689, 26411315, 25256751, 27621404, 28796317, 29667044, 32426482)

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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.