Submissions for variant NM_024675.4(PALB2):c.2978C>T (p.Thr993Met)

gnomAD frequency: 0.00002  dbSNP: rs61756146

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213330	SCV000276097	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	The p.T993M variant (also known as c.2978C>T), located in coding exon 9 of the PALB2 gene, results from a C to T substitution at nucleotide position 2978. The threonine at codon 993 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). In another study, this variant was reported in 5/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). This variant was detected in 4/7840 breast cancer cases and 1/7929 healthy controls from Southeast Asia (Ng PS et al. J Med Genet, 2022 May;59:481-491), and was detected in 0/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 1/1189 controls. (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was reported in a 24-year-old female with a history of two primary cervical embryonal rhabdomyosarcomas and ovarian Sertoli-Leydig cell tumor who also had a DICER1 mutation (Cowan M et al. Gynecol Oncol Rep, 2018 Aug;25:94-97). This amino acid position is well 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	RCV000236936	SCV000292660	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a slight decrease in homologous recombination efficiency (Ng 2021); Observed in individuals with breast cancer or cervical rhabdomyosarcoma (Cowan 2018, Ng 2021); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 33811135, 30014022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544190	SCV000633394	uncertain significance	Familial cancer of breast	2022-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 993 of the PALB2 protein (p.Thr993Met). This variant is present in population databases (rs61756146, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232056). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000213330	SCV000690888	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 993 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 reported in at least five individuals affected with breast cancer and one unaffected individual (PMID: 33471991, 33811135). This variant has been identified in 5/251460 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.
CeGaT Center for Human Genetics Tuebingen	RCV000236936	SCV001150864	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267960	SCV002551642	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478799	SCV002796909	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-05-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000544190	SCV004043208	likely benign	Familial cancer of breast	2023-08-18	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].
Baylor Genetics	RCV000544190	SCV004202103	uncertain significance	Familial cancer of breast	2023-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236936	SCV004222326	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00002 (5/251460 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has reported in individuals with breast cancer (PMID: 33811135 (2022), 33471991 (2021)) as well as in unaffected healthy individuals ((PMID: 33811135 (2022), 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.