Submissions for variant NM_024675.4(PALB2):c.740C>G (p.Thr247Arg)

dbSNP: rs587782658

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132073	SCV000187137	likely benign	Hereditary cancer-predisposing syndrome	2023-12-09	criteria provided, single submitter	clinical testing	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211087	SCV000267991	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Invitae	RCV000211087	SCV000290887	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 247 of the PALB2 protein (p.Thr247Arg). This variant is present in population databases (rs587782658, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354). ClinVar contains an entry for this variant (Variation ID: 142706). 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	RCV000132073	SCV000690945	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588870	SCV000699612	uncertain significance	not provided	2016-04-25	criteria provided, single submitter	clinical testing	Variant summary: The c.740C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Thr to Arg. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is not found in 125258 control chromosomes. This variant has been detected in one BrC pt without strong evidence for causality (Thompson_BCR_2015). In addition, one clinical laboratory/reputable database classified this variant as VUS, without evidence to independently evaluate. Because of the lack of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl	RCV000211087	SCV000785497	uncertain significance	Familial cancer of breast	2017-08-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000211087	SCV004019703	uncertain significance	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.