Submissions for variant NM_002878.4(RAD51D):c.568G>A (p.Ala190Thr)

gnomAD frequency: 0.00167  dbSNP: rs80116829

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586998	SCV000149727	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26261251, 25980754, 27443514, 27878467, 25186627)
Ambry Genetics	RCV000115818	SCV000185251	likely benign	Hereditary cancer-predisposing syndrome	2018-10-02	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.
Eurofins Ntd Llc (ga)	RCV000586998	SCV000231658	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205150	SCV000262323	benign	Breast-ovarian cancer, familial, susceptibility to, 4	2025-02-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000205150	SCV000488990	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-07-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001818278	SCV000602162	benign	not specified	2021-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586998	SCV000698108	benign	not provided	2016-02-15	criteria provided, single submitter	clinical testing
Mendelics	RCV003492496	SCV000839181	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115818	SCV000910663	benign	Hereditary cancer-predisposing syndrome	2015-11-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000205150	SCV001474061	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2023-11-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818278	SCV002071933	likely benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115818	SCV002534828	benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149802	SCV003838194	likely benign	Breast and/or ovarian cancer	2022-05-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205150	SCV004017729	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
CeGaT Center for Human Genetics Tuebingen	RCV000586998	SCV004144441	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	RAD51D: BP4, BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354077	SCV001548604	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Ala190Thr variant was identified in 4 of 9622 proband chromosomes (frequency: 0.0004) from individuals or families with ovarian cancer, breast cancer, or Lynch syndrome and was not identified in 5544 control chromosomes from healthy individuals (Song 2015, Yadav 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs80116829 as "With other allele") and ClinVar (2x as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; 2x as likely benign by GeneDx and Ambry Genetics; and 3x as uncertain significance by Counsyl, EGL Genetic Diagnostics, and Quest Diagnostics Nichols Institute). The variant was not identified in Cosmic. The variant was identified in control databases in 135 of 274972 chromosomes at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 126 of 23588 chromosomes (freq: 0.005), Other in 1 of 6420 chromosomes (freq: 0.0002), Latino in 6 of 34238 chromosomes (freq: 0.0002), European in 1 of 125754 chromosomes (freq: 0.000008), and South Asian in 1 of 30414 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ala190 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.