ClinVar

Description

Variant summary: NBN c.1262T>C (p.Leu421Ser) 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 0.00037 in 260122 control chromosomes in the gnomAD database, including 1 homozygote. The variant was also reported in 7 European American women older than age 70 years who have never had cancer. This data provide supporting evidence for a benign role. c.1262T>C has been reported in the literature in individuals affected with CVID, OvC, HBOC, Lynch syndrome and PDAC (e.g. Offer_2010, Ramus_2015, Tung_2015, Yurgelun_2015, 2017, Chaffee_2018, Dorling_2021) but it was also reported in multiple controls (Offer_2010, Ramus_2015, Dorling_2021). Additionally, evidence of non co-segregation with disease was provided through the study of a large family affected with different types of cancer including breast cancer (Tsai_2019), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and eight ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.