Submissions for variant NM_024675.4(PALB2):c.2869A>C (p.Lys957Gln)

gnomAD frequency: 0.00001  dbSNP: rs515726103

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212818	SCV000211525	uncertain significance	not provided	2021-11-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast cancer (Tischkowitz 2012, Kluska 2017); This variant is associated with the following publications: (PMID: 28279176, 22241545, 25991819, 24485656, 19609323, 20871615)
Ambry Genetics	RCV000160848	SCV000215397	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	The p.K957Q variant (also known as c.2869A>C), located in coding exon 9 of the PALB2 gene, results from an A to C substitution at nucleotide position 2869. The lysine at codon 957 is replaced by glutamine, an amino acid with similar properties. This alteration was observed in 1/559 women with contralateral breast cancer and in 0/565 women with unilateral breast cancer in a case-control study (Tischkowitz M et. al. Hum. Mutat. 2012 Apr;33:674-80). This alteration was also reported in 1 of 460 BRCA1/2-negative women with early-onset breast cancer (Kluska A et al. BMC Med Genomics. 2017 Mar;10:14). 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.
Invitae	RCV000114573	SCV000255092	uncertain significance	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 957 of the PALB2 protein (p.Lys957Gln). This variant is present in population databases (rs515726103, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22241545, 30584090, 35610400). ClinVar contains an entry for this variant (Variation ID: 126694). 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 not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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.
Mendelics	RCV000160848	SCV000839011	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764046	SCV000895000	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160848	SCV000911945	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 957 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 a three individuals affected with breast cancer (PMID: 22241545, 28279176) and ovarian cancer (PMID: 30584090) and in a breast cancer case-control meta-analysis in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010131). This variant has been identified in 4/251406 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.
Sema4, Sema4	RCV000160848	SCV002530733	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000114573	SCV003807272	uncertain significance	Familial cancer of breast	2022-04-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2, BP4 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226198	SCV003923193	uncertain significance	not specified	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2869A>C (p.Lys957Gln) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251406 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2869A>C has been reported in the literature in individuals affected with breast or ovarian cancer without strong evidence of causality, as well as unaffected controls (Dorling_2021, Gonzalez_2022, Kluska_2017, Li_2019, Tischkowitz_2012). These reports do not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Leiden Open Variation Database	RCV000114573	SCV001193308	uncertain significance	Familial cancer of breast	2019-12-04	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.