Submissions for variant NM_024675.4(PALB2):c.1189A>T (p.Thr397Ser)

gnomAD frequency: 0.00003  dbSNP: rs367578415

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130855	SCV000185754	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-20	criteria provided, single submitter	clinical testing	The p.T397S variant (also known as c.1189A>T), located in coding exon 4 of the PALB2 gene, results from an A to T substitution at nucleotide position 1189. The threonine at codon 397 is replaced by serine, an amino acid with similar properties. This alteration has been reported in breast and pancreatic cancer patients as well as in a cancer-free control (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11; Decker B et al. J Med Genet, 2017 11;54:732-741). A functional analysis assessing the impact of missense alterations in the PALB2 chromatin association motif (ChAM) demonstrated that this alteration does not appear to impair or hinder chromatin association (Bleuyard JY et al. Wellcome Open Res. 2017 Nov 14;2:110). This alteration was also found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 03;22:622-632). 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.
GeneDx	RCV000586638	SCV000211553	uncertain significance	not provided	2024-01-08	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; Published functional studies demonstrate no damaging effect: homology directed repair activity similar to wild-type (PMID: 31636395); Observed in individuals with breast and pancreatic cancer, but also in control populations (PMID: 17200668, 26483394, 26283626, 28779002); This variant is associated with the following publications: (PMID: 26483394, 17200668, 26283626, 29387807, 28779002, 22193777, 31636395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205533	SCV000261612	uncertain significance	Familial cancer of breast	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 397 of the PALB2 protein (p.Thr397Ser). This variant is present in population databases (rs367578415, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and pancreatic cancer (PMID: 17200668, 26283626, 26483394). ClinVar contains an entry for this variant (Variation ID: 142048). 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%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000205533	SCV000267997	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000130855	SCV000685858	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 397 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). A functional study has shown that this variant does not affect homology-directed repair activity of the PALB2 protein (PMID: 31636395). This variant has been reported in an individual affected with pancreatic cancer (PMID: 26483394) and in a breast cancer case-control meta-analysis in 8/60466 cases and 5/53461 unaffected individuals (PMID:3347191; Leiden Open Variation Database DB-ID PALB2_010819). This variant has been identified in 5/282346 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. Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267878	SCV000699522	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1189A>T (p.Thr397Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 257098 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1189A>T has been reported in the literature in individuals affected with breast cancer and pancreatic cancer (e.g. Rahman_2007, Thompson_2015, Hu_2015, Decker_2017) but also in healthy control individuals (e.g. Rahman_2007, Thompson_2015, Decker_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homology directed DNA repair versus the WT protein (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 17200668, 26283626, 31636395, 28779002). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as uncertain significance and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000205533	SCV000785634	uncertain significance	Familial cancer of breast	2017-10-17	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000205533	SCV002526034	uncertain significance	Familial cancer of breast	2022-04-20	criteria provided, single submitter	clinical testing	The PALB2 c.1189A>T (p.Thr397Ser) missense change has a maximum subpopulation frequency of 0.0039% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in individuals with breast (PMID: 17200668, 26283626), pancreatic (PMID: 26483394), and ovarian cancers (PMID: 32546565), as well as in control individuals (PMID: 17200668, 26283626). It is reported to be in one woman older than 70 years of age without cancer (FLOSSIES database, https://whi.color.com/). A functional study demonstrates that this variant has homology directed repair activity similar to the wild-type (BS3; PMID: 31636395). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267878	SCV002551682	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149904	SCV003838717	uncertain significance	Breast and/or ovarian cancer	2022-08-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205533	SCV004019680	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	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].
Genetics and Molecular Pathology, SA Pathology	RCV003447500	SCV004175336	uncertain significance	Familial ovarian cancer	2021-03-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000205533	SCV004202035	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584197	SCV005068368	uncertain significance	Inherited breast cancer and ovarian cancer	2024-05-10	criteria provided, single submitter	clinical testing	BP1